every person's guide to antioxidants
TRANSCRIPT
everyperson'sguidetoantioxidants
JOHNR.SMYTHIESM.D.F.R.C.P.
RUTGERSUNIVERSITYPRESSNEWBRUNSWICK,NEWJERSEY,ANDLONDON
title: EveryPerson'sGuidetoAntioxidantsauthor: Smythies,JohnR.
publisher: RutgersUniversityPress
isbn10|asin: 0813525756printisbn13: 9780813525754ebookisbn13: 9780585023083
language: English
subjectOxidation,Physiological,Antioxidants--Healthaspects,Freeradicals(Chemistry)--Pathophysiology.
publicationdate: 1998lcc: RB170.S691998ebddc: 616.07
subject:Oxidation,Physiological,Antioxidants--Healthaspects,Freeradicals(Chemistry)--Pathophysiology.
LibraryofCongressCataloging-in-PublicationData
Smythies,JohnR.(JohnRaymond),1922-Everyperson'sguidetoantioxidants/JohnR.Smythies.p.cm.Includesbibliographicalreferencesandindex.ISBN0-8135-2574-8(alk.paper).-ISBN0-8135-2575-6(pbk.:alk.paper)I.Oxidation,Physiological.2.Antioxidants-Healthaspects.3.Freeradicals(Chemistry)-Pathophysiology.1.Title.RB170.S691998616.07-dc2198-6810CIP
BritishCataloging-in-PublicationinformationavailableCopyright©1998byJohnR.SmythiesAllrightsreserved
Nopartofthisbookmaybereproducedorutilizedinanyformorbyanymeans,electronicormechanical,orbyanyinformationstorageandretrievalsystem,withoutwrittenpermissionfromthepublisher.PleasecontactRutgersUniversityPress,LivingstonCampus,100JoyceKilmerAvenue,Piscataway,NewJersey08854-8099.Theonlyexceptiontothisprohibitionis"fairuse"asdefinedbyU.S.copyrightlaw.
ManufacturedintheUnitedStatesofAmerica
forVanna
contentsIntroduction 1
part1
thebasics:oxygen,reactiveoxygenspecies,andoxidativestress
5
part2
theroleofoxidativestressandantioxidantsinhealthanddisease
17
part3
thesafetyofantioxidantsandrecomendations 89
APPENDIX 109
ABREVIATIONS 111
REFERENCES 113
INDEX 127
acknowledgementsIammostgratefultoLesleySmythiesforherexcellentandpainstakingeditorialworkonthisbookandheradviceaboutimmunology;toChristopherSmythiesforhelpfulcommentsfromthepointofviewofneurosurgeryandforsupplyingtheepitaphfromTombstone;andtoVannaSmythiesforhelpinadjustingthematerialforthelayreader.IshouldalsoliketothankmydedicatedagentJuliePopkin;CharlesThomasofPantoxLaboratories,SanDiego;JessicaHornikEvans,copyeditor;andDoreenValentineofRutgersUniversityPressforherskilledandtirelesseditorialguidance.IshouldalsoliketorecordthedebtthatweallowetotheIrelandfamilyofBirmingham,Alabama,pioneersintheactivesupportofpromotingtheimportanceofantioxidantvitaminsinhealthanddisease.
everyperson'sguidetoantioxidants
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introductionWeliveinanageinwhichmillionsofpeopleintheUnitedStatesandelsewheretakevitaminstosupplementtheirdietunderthebeliefthatthesewillhelptomaintaingoodhealthandwardoffillness.Anenormousindustryformanufacturing,packaging,anddistributingvitaminshasgrownuptomeetthisneed.IntheUnitedStatestherearemorethaneleventhousandhealth-foodstoresandnutritioncentersthatsellonlyvitaminsandrelatedproducts.Furthermore,nearlyeverydrugstoreandsupermarkethasanextensiveareadevotedtovitaminpreparations,ofwhichtherearehundredsofvarietiesandbrandnames.Thesevitaminsaresoldeitherasmixturesofmultivitaminsandessentialmineralsorindividually.Amongthe"special"typesofvitaminsthatfilltheseshelvesarethoselabeled"antioxidants."TheseincludesuchfamiliarvitaminsasA,C,E,andbeta-carotene.Lesswell-knownantioxidantsincludemelatonin,lycopene,zeaxanthin,andvariousflavonoids.
Newspapers,magazines,andtalkshowsarebrimmingwithdiscussionsofantioxidants.Theseaccountsclaimthatantioxidantsareeffectiveinhelpingtopreventcancer,heartdisease,andotherchronicillnesses.Butthemassmediaalsocarryreportsonsomeallegedalarmingsideeffectsofantioxidants.
Forexample,theNovember25,1996,issueofTimemagazinecarriedalongarticlecalled"CanWeStayYoung?,"whichstatedthat,althoughsomenutritionistshaverecommendedadiethigh
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infruitsandvegetablesthatcontainantioxidantstocombatdisease,thisapproachhasan"unevenrecord."Accordingtothearticle,insomestudiestheuseofantioxidantsappearstobeassociatedwitha"dramatic"reductionincancerandotherdiseases,butinotherstudiesbeta-carotene(theonlyantioxidantmentionedbynameinthearticle)actuallyseemstobeassociatedwithanincreaseincancer.Thearticleconcluded:"Ineithereventfewcontemporaryagingresearchersthinkself-medicatingatasaladbaristhebestwaytoextendthehumanlifespan."Thisreportisseriouslymisleading,asthisbookshows,andindicatesthelevelofconfusionthatthepublicfaceswithregardtothescienceofantioxidants.TheMarch1997issueofConsumerReportscarriedasectiononantioxidantsthatalsoprovidedconsumerswithconflictinginformation.ThearticlecorrectlystatedthatvitaminEhadbeenshowntobeprotectiveagainstheartattacksbutcastdoubtontheeffectivenessofbeta-caroteneandvitaminCasprotectiveagents.However,thearticleneglectedtomentionamostimportantfact:antioxidantsshouldalwaysbegivenasawell-balancedmixture(eitherinthedietorassupplements)andnotsingly.InitsAugust1997issue,ConsumerReportshadasectiononmethodsthatwomenshouldusetoreducetheirriskofaheartattack.Itfailedtomentionanydietaryfactorsotherthanalowfatandalcoholintake.
TheNationalAcademyofScienceshasformanyyearspublishedalistofrecommendeddailyallowances(RDAs)forthecommonvitamins.Forexample,thecurrentRDAforvitaminCis60mgperdayandforvitaminE,20mgperday.Butfrequentlythedosagesofvitaminspertabletonthemarketcontainmanytimestheamountoftherecommendeddailyallowance.Whyso?Sometwenty-fiveyearsagoNobelLaureateLinusPaulingclaimedthatpeoplewouldbenefitiftheytook"megadoses"ofvitamins.Hisargumentwasthattherecommendeddailyallowancesreflectedonlywhatwasneededtoavoidspecificvitamindeficiencydiseasessuchasscurvy,pellagra,
andberi-beri.Whatisreallyneeded,heclaimed,is"optimum"doses:if10mgofavitaminisbeneficial,then100mgisboundtobetentimesbetter.Althoughtherewaslittleevidencetosupportthisclaimatthetime,itsoonbecameapopularbeliefandthebasisformarketingmegavitamins.Paulingwascorrectinhisobservationthattherecommendeddailyallowancesofvitaminstodayarecalculatedonthebasisoftheamountneededtoavoiddeficiencydiseases,
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buthenevergaveanyconvincingreasonforhisideaofoptimumlevelsofintake.Pauling'sideaswerenotreceivedwithenthusiasmbythemedicalestablishment;infact,thegeneralopinionwasthattheyamountedtoquackery.Wehavenowcometorealize,onthebasisoffactsthatwerenotknowntwenty-fiveyearsago,thattheamountofeachantioxidantvitaminneededtoavoiddeficiencydiseasesisindeednotthesameastheamountthatahealthybodyneeds,asDr.LelandTolbertandIpointedoutinapaperpublishedin1981[193].Thisisbecauseantioxidantvitaminsplayaveryimportantroleinthebodythatisquitedistinctfromtheirparticularroleinpreventingscurvyandotherdeficiencydiseases:theyprovidethebodywithitsownantioxidantdefenses.ItwouldbefittingtoreevaluatetheroleofLinusPaulinginmedicine.AfamousepitaphonagravestoneinaTombstone,Arizona,cemetery,sumsupthissituationwell:"HereliesthebodyofGeorgeThompson/Hungformurder1882/Hewasrightandwewaswrong/Butwestrunghimup/andnowhe'sgone."
Althoughwe'veallheardtheterm"antioxidants,"manypeoplearenotveryclearaboutwhatantioxidantsare,whattheyaresupposedtodo,andif-andwhenandwhy-itisadvisabletotakethem.Thisbookdescribeswhatantioxidantsareandhowtheywork.Tohelpthereaderunderstandtheroleplayedbyantioxidants,Idiscussoxidativestress,whichisduetotheoverproductionofpotentiallyharmfuloxidantsinthebody.Itisthejobofantioxidantstocounteractthedeleteriouseffectsofharmfullevelsofoxidants.Oxidantsplaymanynormalrolesinthebody;itisonlytheiroverproduction(orthefailureofantioxidantdefenses)thatresultsinharmfuloxidativestress(i.e.,disease).Antioxidantsmaybetakeneitherbyhealthypeopleinanattempttowardoffthedevelopmentofchronicdiseaseslikecancerandheartattacks,orbysickpeoplewhoarefacingadiseaseforwhichthereisevidencethatantioxidanttherapywillhelp.Iexploreindepththerelationshipbetweenoxidantsandoxidativestressanddiseaseand
lookathowantioxidantsmayfunctiontopreventorcombatdisease.
Manyscientificexperimentsandclinicaltrialshavebeencarriedouttotesttheideathatantioxidantsareimportanttomaintaingoodhealth.InthisbookIreviewthecurrentmedicalandscientificliteratureonoxidativestressandantioxidantsandpresentthemostimportantoriginal
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datafromthesescientificexperimentsandclinicaltrials,withtheirgoodandbadpoints.Itismyhopeisthat,armedwithanunderstandingoftheresearchandafairevaluationoftheresultsaspresentedhere,thereaderwillbeabletodecideforhim-orherselfastotheneedtotakeantioxidants.Suchadecisionwillbebasedoninformedknowledgeofthefactsratherthanonthepropagandaputoutbyuncriticalenthusiastseitherfororagainsttakingantioxidantsupplements.Thisinformationwillalsoenablethereadertodiscussantioxidantswithadoctor.Itisstillunfortunatelytruethatmanyphysicianshavenotkeptupwiththerecentadvancesinthisfield,whichisstillregardedbysomeastaintedwiththe"alternativemedicine"stigma.Forthoseinthehealthprofessions,thisbookwillhelpestablishthatantioxidantsareimportantforthecareofpatients.
Mycredentialsforwritingthisbookderivefrommanyyearsofscientificresearchonoxidativestressandantioxidants.Inparticular,Ihavestudiedtherolethatoxidativestressplaysinschizophrenia;Iwasthecodeveloperin1952ofthefirstspecificbiochemicaltheoryofschizophrenia-thetransmethylationhypothesis.In1954Dr.AbramHoffer,Dr.HumphryOsmond,andIdiscoveredthatanoxidizedderivativeofepinephrine,oneofthehormonesthatissecretedbytheadrenalglandandisalsofoundinthebrain,producespsychoticsymptomsinnonpsychoticvolunteers[89].Althoughmyworkhasfocusedontherelationshipbetweenoxidativestressandpsychiatricillness,Ihavealsostudiedtheroleofoxidativestressandantioxidantsinalldiseases.
Thisbookisdirectedatallpeopleinterestedinthequestionofwhethertheyneedtochangetheirdietinordertoimprovetheirlong-termhealthandwhethertheyalsoneedtotakeantioxidantsupplementstodoso.Itisalsodirectedathealthprofessionalsinvolvedinpreventativemedicineandintreatingthediseasescoveredinthebook.Thisbookwillalsobeofinteresttothosewhoworkfor
governmenthealthprograms,includingMedicare,andnongovernmentorganizationsconcernedwithhealthcaredelivery;thehealthinsuranceindustry;andanyotherswhoareresponsibleforpublichealthpolicyandfunding.Themeasuresthisbooksupportshavethepotentialnotonlytoreducetheamountofchronicdiseasessufferedbypeoplebutalsosubstantiallytoreducethecurrentcripplingcostsofmedicalcare.
Knowledgeofchemistryisnotnecessarytoreadthisbook.
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part1thebasics:oxygen,reactiveoxygenspecies,and
oxidativestressbeforewecantalkclearlyaboutwhatantioxidantsareandhowtheypreventdisease,weneedtoconsidersomebasicconceptsaboutthebody'scellsandorgans.Everycellinthebody-whetheraheartcell,alivercell,orabraincell-functionslikeaminiaturechemicalfactory.Alargenumberofdifferenttypesofchemicalreactionsoccurwithinthecell,leadingtothebreakdownoflargecomplexmoleculesintosmallerproductsortothesynthesisofnewmoleculesfromsmallerbuildingblocks.Otherchemicalreactionsoccurthatmayleadtothetransferofsmallelectricalchargesfromonechemicalsubstancetoanother.Amongthesetransferreactionsareoxidation-inwhichanegativelychargedparticlecalledanelectronislost-andreduction,inwhichtheelectronisgained.Burningisoneformofoxidation,aswhencoal(carbon)burnstoformcarbondioxide.Butamoregeneralformofoxidationinvolvesthistransferofelectronsfromonemoleculetoanother.
Curiouslyenough,oxidativestressarisesinevitablyfromthechemistryofthelife-givingmoleculeofoxygen.Exceptfor
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someveryprimitivebacteria,oxygenisessentialforlifeandprovidestheenergyonwhichallcellsinthebodyoperate.Thatisthegoodnews.Thebadnewsisthattheordinaryoxygenmoleculeeasilyturnsintooxidizingagents,calledreactiveoxygenspecies,thatpossessgreatpotentialdanger.Insimpletermsoxidizingagents(alsocalledpro-oxidants)areshortofelectrons(eachatomhasanucleus,composedofprotonsandneutrons,surroundedbynegativelychargedelectrons)andwillstealthemfromanyneighboringmoleculeinthebodythatdoesnotkeepatightholdonitsownelectrons.Thisdamagestheneighboringmoleculeseverely.Commonhouseholdbleachisanexampleofapowerfuloxidizingagentinwhichtheactiveingredientisthepoisonousgaschlorine.Reactiveoxygenspeciesplaynormalrolesinthebody,butinexcesstheydevelophighlypoisonousproperties.
Themostimportantreactiveoxygenspeciesinthebodyarethesuperoxideion(O-),thehydroxylradical(OH),andhydrogenperoxide(H202).Thestablemoleculeofwaterismadeupoftwoatomsofhydrogenandoneofoxygen(H20).Notethatthehighlytoxichydroxylradicaliscomposedofoneatomofoxygenandonlyoneofhydrogen.Hydrogenperoxide,usedwidelyinhouseholdsasanantiseptic,ismadeupoftwoatomsofhydrogenandtwoatomsofoxygen.Thesereactiveoxygenspeciesareallshortofelectronsandarethuspowerfuloxidizingagents.Hydrogenperoxideisactuallysomewhatdifferent,asitisnotitselfshortofelectronsbuteasilyconvertsinthebodytocompounds,suchasthehydroxylradical,thatareshortofelectronsandthatdothedamage.Technically,compoundsthatareshortofelectronsarecalledfreeradicals.Thesuperoxideionandthehydroxylradicalarefreeradicals.Thus,reactiveoxygenspeciesincludebothoxygen-derivedfreeradicalsandcompoundslikehydrogenperoxidethatarenotthemselvesfreeradicalsbutthateasilygeneratethem.Leftfreetoreactinthebody'stissues,reactiveoxygen
specieswillattackanddamagekeymoleculesinthebody,suchasfats,proteins,andDNAthemoleculethatcarriesgeneticinformation.
Tounderstandwhyreactiveoxygenspeciesarepotentiallysoharmfulforcells,wehavetolookabitmorecloselyatthecellitself.Eachcellinthebodyiscomposedofamembraneboundary,afluidinterior,andacentralnucleus,alongwithasetofothersmallstructurescalledorganelles.Themembraneofthecellismadelargelyoffat.Whenthefatsinthemem-
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braneareoxidizedbyareactiveoxygenspecies,themembranebecomesbrittleandleaky;eventually,itfallsapartandthecelldies.Thisisalotlikebutterturningrancid,whichhappenswhenthefatsinbuttergetoxidized.Hencedairiesputantioxidantsinthebuttertopreventthisfromhappening.Proteinsarelocatedeitherembeddedinthefattymembraneorthroughouttheinteriorofthecell.Manyproteinsaresmallmachinesthatperformimportantfunctionsinthecell.Otherproteinshaveapurelystructuralrole.Someproteinsareenzymesthatmanufacturesubstancesneededbythecell,andsomearehormonesthatactassignalstoothercells.Otherscontroltheentryandexitofsubstancesacrossthecellmembrane.Whenareactiveoxygenspeciesattacksaproteinanddamagesit,somekeyfunctionofthecellwillbejeopardized.DNA,themoleculethatcarriesthegeneticinformationofthecell,isfoundinthecell'snucleus.Oxidativedamagetoitcancausemutationsthatpredisposethecelltocancerformation.Intheseways,throughdamagetofats,proteins,andDNA,variouspartsofthebodycanbeweakenedbyoxidativeattackandwillsuccumbtoawidevarietyofdiseases.Iexplainthisfullyinpart2.
Ifoxidizingagentsaresoharmfultocells,wehavetoaskwhynaturewouldhaveproducedacellularsystemthatmanufacturesthem.Indeed,severalessentialbiochemicaloperationsinthebodygeneratereactiveoxygenspeciesasapartoftheessentialmechanismbywhichtheywork.Takeseveralexamples:
1.Thebasicmechanismofenergyproductionofthecellproducesreactiveoxygenspeciesasaninescapableby-productofthenecessarychemistryinvolved.Ithasbeenestimatedthat10percentoftheoxygenwebreatheisturnedintoreactiveoxygenspeciesduringthisprocess.
2.Thejobofsomewhitebloodcellsofthebody'simmunesystemis
toattackandkillinvadingpathogenicbacteriaandviruses.Oneweapontheyusetodothisishighlypoisonousreactiveoxygenspecies.
3.Duringtheprocessofinflammationasetofchemicalscalledprostaglandinsissecreted.Prostaglandinscausetheredness,pain,andswellingassociatedwithinflammation.Theyareinvolved,forexample,ininfections,burns,andarthritis.Akeyenzyme(calledprostaglandinHsynthase,orPGHsynthaseforshort)thatmakesthem
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generateslargeamountsofreactiveoxygenspeciesasaby-product.Aspirinworksbyswitchingoffthisenzyme.Thisresultsinlessprostaglandin-inducedpainandswelling.
4.Asthebraindevelops,manymorenervecellsandmanymoreconnectionsbetweenthemaremadethanareactuallyneeded.Asthebraingrowsduringchildhood,theexcessnumbersoftheseareprunedaway.Duringthisprocessreactiveoxygenspeciesmoleculesareprobablyusedasapruningagenttokilltheunwantedcells.Duringthelearningprocessinadultsaswellasinchildren,manynewconnectionsbetweennerves(calledsynapses)aremadeandold,failed,onesremoved.Reactiveoxygenspeciesareprobablyinvolvedintheselectiveremovalofunwantedsynapses(asisdiscussedlaterinmoredetail).ReactiveoxygenspeciesalsohavenormalfunctionsinrelationtothecontrolofDNAaction.TheydothisbyactivatingamoleculecalledNF-KB.Thismoleculeswitchesonanumberofgenes,includingthoseresponsibleformakingkeymoleculesconcernedininflammation.Thepresentfocusofattentionofresearchersisontheroleofreactiveoxygenspeciesinthemechanismsbywhichcellssignaltoeachotherduringtheinflammationprocess[222].Theindirectfunctionofreactiveoxygenspeciesoperatesinadditiontothedirectattackbyreactiveoxygenspeciesonproteins,fats,andDNA.Thisnewresearchisimportant,asabnormalitiesinNF-KBactivationareinvolvedinatherosclerosis,Alzheimer'sdisease,HIVinfection,rheumatoidarthritis,asthma,andotherdisorders.
Theseprocessesillustratethefactthatreactiveoxygenspeciesarenotalwaysvillainsbuthavesomenormalfunctionsinthebody.Itisonlywhenthereissomedisturbanceinthissystemthatdiseaseresults.SimonianandCoyle[185]giveagraphicaccountofoxidativestressas''anexpanding,self-perpetuating,andreinforcingseriesofmetabolicevents,whichpromotethegenerationof[more]reactive
oxygenspeciesandimpairpotentialprotectivemechanisms.Likeaspreadingwildfire,thesiteoftheinitiatingsparkmaybeobscuredinitsterminalstages."
Oxidativestresscanresultfromfourmaincauses:(1)Reactiveoxygenspeciescanbeingestedinexcessfromsomeenvironmentalsource(suchastobaccosmokeordieseloilfumes);(2)thedietmaycontaininsuffi-
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cientantioxidants;(3)theremaybesomedisturbanceintheelaboratebiochemicalsystemsthatcontroltheirproductionanddistribution(asinthecaseofmanydiseases);(4)theremaybeafailureinprotectiveantioxidantmechanisms(asinthecaseofmanyotherdiseases).Thetopicofoxidativestressisdealtwithindetailinpart2.
antioxidantsThebiochemicalreactionsthatproducereactiveoxygenspeciesareessentialforlifeandcanbetracedveryearlyoninevolution.Theyarefoundincellsrangingfrombacteriatohumancells.But,aswediscoveredabove,theseessential,naturallyoccurringsubstancescanalsodamageandkillcells.Sohowisitthatcellssurvivedespitetheconstantonslaughtofreactiveoxygenspecies?Theansweristhatevolutionhadtoproduceefficientdefensesthatwouldpreventreactiveoxygenspeciesfromkillingthecells.Thesedefensesconsistofasetofspecializedmoleculesknownasantioxidants.Astheirnamesuggests,antioxidantsfunctiontopreventthedamagetocellsthatwouldotherwiseoccurasaresultofanattackbyreactiveoxygenspecies.
tounderstandhowantioxidantsperformtheirroleandwhydifferenttypesareneeded,wemustreturntothestructureofthecellitself.Theinteriorofthecellandthefluidbetweencellsarecomposedmainlyofwater.Thecellmembrane,aswehaveseen,ismadelargelyoffat.Asweknowfromexperience,oilandwaterdonotmix.Chemicallyspeaking,thegeneralruleisthatsubstancesthataresolubleinwaterarenotsolubleinfat,andviceversa.
Asoxidantscanstrikeeitheratthefattycellmembraneoratthewaterycellcontents,antioxidantsareneededthatwillworkeitherinthefattymembraneorinthewaterycompartments.Inotherwords,
thecellneedstohaveavailableantioxidantsthataresolubleinwaterandothersthataresolubleinfat.Besidessolubility,anotherwayinwhichantioxidantsdifferfromeachotherissize.Someantioxidantsaresmallmolecules,whereasothersarelargeproteins.Thesmallmoleculetypesworkinpartbymoppingupor"scavenging"thereactiveoxygenspeciesandcarryingthemaway,andinpartbyneutralizingthemchemically.Theproteinantioxidantsareeitherenzymesthatturnreactiveoxygenspeciesinto
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harmlesssubstances,ortheyareinessential"sacrificial"proteins(likealbumin).Asacrificialproteinwillabsorbreactiveoxygenspeciesandthuspreventthemfromattackingsomeessentialprotein.
Thebodygetsitsessentialantioxidantsfromtwomainsources:someantioxidantsareproducedinthebodyitself,whereasothershavetobeobtainedfromthediet.Someofthedietaryantioxidantsarecalledvitamins-meaning"vitalamine"-becausetheyareessentialforlife,andlowlevelsoftheminthedietcausedeficiencydiseasessuchasscurvyandpellagra.Thereareotherdietaryantioxidantsthatthebodycannotsynthesize,butthesearenotessentialforlife,andtheirabsenceinthedietdoesnotleadtodisease.Forthisreasontheseantioxidantsarenotcalledvitamins.Althoughtheyarenotessentialingredientsinthediet,theyareneverthelesshelpfulincombatingoxidativestress.
SMALL-MOLECULEANTIOXIDANTS
Ofthesmall-moleculetypesthechiefwater-solubleantioxidantsarevitaminCandglutathione.VitaminC,whosechemicalnameisascorbicacidorascorbate,isarelativeofthesimplesugarglucose.Glutathione,alessfamiliaralthoughjustasimportantantioxidant,isasmall,proteinlikemolecule.HumanscannotmaketheirownvitaminC,sowemustacquireitfromourdiet;butmostanimalscanproducetheirownvitaminC.Allanimals,includinghumans,canmakeglutathione.Whennaturallevelsofglutathionearelow,N-acetylcysteine(NAC)canbeadministeredclinicallyasanantioxidant.Aprecursormolecule,NACisturnedintoglutathioneinthebody.Inthebrain,vitaminCisthemainantioxidantinthefluidbetweennervecells,andglutathioneisthemainantioxidantinsidethem.
Themainfat-soluble,small-moleculeantioxidantsarevitaminE,variouscarotenes(relativesofvitaminA),lipoicacid,andvitamin
Q10.VitaminEisalpha-tocopherol.Ithasarelative-gamma-tocopherolthatisalsoasignificantantioxidant.VitaminEalsoboostsimmuneresponses,bothbyprotectingthemembranesoftherapidlydividingimmunecellsinthetissuesfromoxidativestressandbyprotectingthesympatheticnervesinthelymphoidtissue,wheretheimmunecellsareformed,againstoxidativestress.
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Thecarotenesaretheredandyellowpigmentsfoundinredandyellowvegetables;thebestknownisbeta-carotene.However,only25percentofthecarotenesinthedietconsistofbeta-carotene.Beta-caroteneisparticularlyimportantintheovary,whereitisfoundinveryhighconcentrationinthecorpusluteum,theovarianstructurethatsustainspregnancybymakingthekeypregnancyhormoneprogesterone.Thereareoverfivehundredothercarotenesfoundinfruitsandvegetablesinthediet,themostimportantofwhicharelycopene,reservatol,zeaxanthin,andlutein.LipoicacidregeneratestheactiveformsofvitaminsCandE.Itisfoundindarkgreenleafyvegetables.
Small-molecule,fat-solubleantioxidantshavetobeobtainedfromplantsbecauseanimals,includinghumans,cannotmakethem.Inthecaseofthisclassofantioxidants,therearesignificantchemicaldifferencesbetweenthenaturalformsfoundinplantsandtheformssynthesizedbychemists.Thenaturalformconsistsofonestereoisomer,thesyntheticvarietyofeight.Thevariousstereoisomershavethesamechemicalformulabutareputtogetherdifferentlyandmayhavedifferentbiologicalactivities.VitaminQ10isfoundinmeat,withhighlevelsinorganmeatssuchasliverandkidney.Otherimportantantioxidantsinthebody,particularlyintheblood,areuricacidandbilirubin;melatonin,apowerfulantioxidantproducedbythepinealgland,isinvolvedintheregulationofsleep.
LARGE-MOLECULEPROTEINANTIOXIDANTS
Someofthelarge-moleculeantioxidantsareenzymesthatturnreactiveoxygenspeciesintoinactiveproducts.Themainonesaresuperoxidedismutase(SOD),whichdetoxifiesthesuperoxideion(O-);catalase(CAT),whichdealswithhydrogenperoxide(H202);andglutathioneperoxidase(GSHpx),whichtakescareofseveraltypesofreactiveoxygenspecies.Theseareallessentialenzymesandare
synthesizedinthebody'scells.Otherlarge-moleculeantioxidantsarelargeinessentialproteins(likeserumalbumin)thatmopupreactiveoxygenspeciesandgetdamagedintheprocess.Their"sacrificial"functionprotectsessentialproteins,likeenzymesandDNA,bygettinginthewayofthebullet,asitwere.
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SYNTHETICMOLECULES
Thedrugindustryisbusymakingnewsyntheticantioxidantsthatmaybemoreeffectivethanthenaturalonesincombatingdisease.Theseincludesteroids(suchasthelazaroidgroup),fat-solublederivativesofvitaminC,mifepristone,andmanyothers,someofwhicharementionedlaterinthisbook.
SYNERGISMBETWEENANTIOXIDANTS
VitaminCactsbothonitsownandincooperationwithvitaminE.Itdoesthelatterbecause,whenvitaminEhasmoppedupareactiveoxygenspecies,thevitaminEisitselfoxidized.And,tobeeffective,thisoxidizedvitaminEmustbeturnedbacktotheactiveform;thisiswhatvitaminCdoes.OncethevitaminChasbeenoxidized,ittoomustbeturnedbacktoitsactiveform.ThisisdonebyanothercompoundthatincludesaformofvitaminB(nicotinamide)initsmolecule.Thus,thenicotinamideformofvitaminBalsohasindirectantioxidantproperties.Thischainlikehelpingorsynergisticprocesshasimportantconsequences.
CarotenoidsarealsoinvolvedinrecyclingvitaminEinanotherchain:vitaminE-carotenoid-vitaminC.However,vitaminChasimportantantioxidantfunctionsonitsowninadditiontoitsconnectionwithrecyclingvitaminE.
IMPORTANTANTIOXIDANTSFOUNDINPLANTS
Flavonoidsandphenols(whichtogetherarealsocalledphytochemicals)formalargeclassofnaturalantioxidantspresentinmanyplants,withmorethansixhundredantioxidantphytochemicalshavingbeendetected.Richsourcesoftheseagentsaretea,garlic,oliveoil,andmanyherbs,fruits,andvegetables.IthasbeenestimatedthattheaveragedailyintakeoftotalflavonoidsintheUnitedStatesis
about500mg.Theyactinseveralways-bymoppingupreactiveoxygenspeciesandtoxicheavymetals,bypreventingtheformationofreactiveoxygenspeciesandfatoxidation,andbyprotectingotherantioxidantssuchasvitaminC.TheyalsoinhibitLDL(badcholesterol)oxidation,therebysparingthepreciousvitaminE.However,onceallthevitamin
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Ehasbeenconsumedbyanoxidativeattack,flavonoidsfailtoinhibitfatoxidation.ThissuggeststhattheiractionisdependentonthepresenceofvitaminE-thatis,theybelongtothegroupofvitaminE"helpers."Buttheyactinmanyotherwaysbesidesbeingantioxidants.Manyflavonoidsinteractwithcytokines(keyproteinsinthecellthatactasmessengers,particularlyinconnectionwithinflammation),andtheyalsoblocktheproductionofinflammatoryprostaglandinsandpreventbloodplateletsfromstickingtogethertoformclots.
Antioxidantflavonoidsincludecatechin(greentea),gossypol(rice),apigenin(chamomiletea),quercetin(apples),hesperetin(oranges),andnaringenin(grapefruit).Antioxidantphenolsincludethymolandcarvacuol(thyme),ferulicacid(manyherbs),gallicacid(nutgall),hydroxytyrosol(oliveoil),fisetin,morin,andmanyothers.Antioxidantpolyphenolsarefoundinoranges(ascryptoxanthin)andmanyotherfruits,tea,coffee,chocolate,licorice,andwhitewine.Otherrelatedplantantioxidantsincluderhein(rhubarb)andaloe-emodin(aloe).Antioxidantpeptides(small,proteinlikemolecules)includecarnosine(whichisparticularlyassociatedwiththeglutamatereceptorinthebrain)andanserine.RosemarycontainscompoundsthatstimulatetheproductionoftheantioxidantglutathioneintheliverandactasantitumorcompoundsthatblockcancerproducingchemicalsfrombindingtoDNA.
SOYBEANS.
Soybeanscontainavarietyofanticancercompounds,suchasgenistin,whichareeffectiveatmoppingupreactiveoxygenspeciesbutarealsolikelytoactinadditionalwaystokillcancercells.Genistinandrelatedcompoundsarealsofoundinwholegraincereals,seeds,berries,andnuts.
REDANDWHITEWINE.
Redwinecontainsuptotwentytimesmoreflavonoidsandrelatedcompoundsthandoeswhitewineandtentimesmorethantea.Theseincludequercetin,rutin,andcatechin.Redwinealsocontainsapotentantioxidant-reservatol-foundalsoinpeanuts.Reservatolslowsthemakingoffatsbytheliverandinhibitsprostaglandinsynthesis(andthusinflammation);italsopreventsplateletsfromstickingtogether(amajorcauseoftheblockageofcoronaryarteriesleadingtoheartattacks).Aderivativeofreservatolisaningredientinafolkmedicinecalled
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kojo-kon.Itisalsofoundinanotherfolkmedicineobtainedfrompolygonumcuspidatum,whichhasbeenusedsinceancienttimesforthetreatmentofheartdisease,allergies,andinflammation.Ithasbeensuggestedthatsomeofthereportedbeneficialeffectsofredwinemayactuallybeattributabletoraisedbloodlevelsofthemajorbloodantioxidanturicacid.Portwineraisesblooduratelevels,butanequalamountofpurealcoholdoesnot.Portdrinkerstendtogetgout,whichstemsfromadisorderofuricacidmetabolism.
TEA.
ThecatechinsandrelatedflavinsinteahavebeenreportedtoinhibitfatoxidationinredcellmembranesandprotectDNAagainsthydrogenperoxide.Ateaantioxidant-epigallocatechingallate-inhibitsoxidativedamagetoDNA.Atest-tubeexperimentshowedthatflavonoidsfromgreenteaprotectedartificialfatbilayermembranesfromfatoxidation.Inthecaseofalcoholicextracts,greenteaismuchmorepotentthanblacktea[224].Therefore,someotherunknownantioxidantcompoundsmustbepresentingreenteathataresolubleinalcoholbutnotinwater.Waterysolutionsofgreenteaandblacktea(whichbothcontainquercetin,myrecetin,andkaempferol)areequallyeffectiveinpreventingfatoxidationintesttubeexperiments.Thesecompoundsalsohaveanticancereffectsinanumberoftests.
GARLIC.
InMediterraneancountriesgarlichasalwaysbeenregardedasahealth-givingfood.ThereisasayinginItalythattolivelongonemusteatplentyofaglio,olio,elimone(garlic,oliveoil,andlemons).Thehealth-givingeffectofgarlicisnotjustfolkwisdom;garliccontainsthepotentantioxidantsallinandallicin,whicharesulphur-containingaminoacids.
OLIVEOIL.
Oliveoilcontainsanumberofantioxidantcompounds(includingbeta-tyrosol,hydroxytyrosol,caffeicacid,andvanillicacid);theconcentrationofthesesubstancesishigherinextravirginoilthaninrefinedproducts.Thebitterprincipleofoliveoil(oleuropein)alsoprotectsLDLsagainstfatoxidation.Apotentphenolicantioxidantinoliveoilhastheeffectofpreventingbloodplateletsfromstickingtogetherandreducestheproductionofinflammation-producingthromboxanes(relativesofprostaglandins).Interestingly,ithasnowbeen
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discoveredthatthewastewatersfromoliveoilproductionareparticularlyrichinanumberofantioxidants.
OTHERPLANTANTIOXIDANTS.
Turmeric,aningredientofcurrypowder,containstheantioxidantcurcumin,apolyphenol.Inanimalexperimentslong-termfeedingofcurcuminsignificantlyreducedtheabilityofcarcinogenstoproducecoloncancer.Yeastandyeastextracts(suchasMarmite)areloadedwithantioxidants(includingglutathioneandvitaminQ10).
Manyherbalmedicineshaveahighcontentofantioxidantphytochemicals.Anayurvedic-theancientfolkmedicineofIndia-drugpreparedfromanumberofplantsismarketedtodayasaproductnamedGeniforte.Inanimalexperimentsthisinducesthesynthesisofantioxidantenzymesandreducestheleveloflipidoxidation.Boldine,aningredientinaChileanfolkmedicinemadefromtheboldotree,isusedforthetreatmentoflivercomplaintsandrheumatism.Verypotentatmoppinguphydroxylradicals,thisantioxidantisnontoxicandnonmutagenic.
Itislikelythatmanyherbalremediesworkbyvirtueoftheirantioxidantcontent,yetthereverseisalsotrue.Someflavonoidshavepropertiesthatdependonactionsunconnectedwiththeirantioxidantproperties.Forexample,ithasbeenshownthatsomeflavonoids,likequercetin,gossypol,chrysin,andapigenin,bindtoacertainreceptorinthebraintowhichbenzodiazepinetranquilizers,suchasValium,usuallybind.Theherbsfromwhichthesecompoundsareobtained(suchaspassifloracoeruleaandmatricariarecutitis)havebeenreportedinfolkmedicinetohavesedativeandpain-relievingproperties.AsyntheticderivativefromtheseflavonoidshasbeenproducedthatisonehundredtimesaspotentasValium[137].Moreover,itlackedsomeoftheannoyingsideeffectsofValium,suchassedationandmusclerelaxation.
ISOPRENOIDS
Thesearenotantioxidantsbutanticanceragentsthatretardtumorgrowthbyinhibitingcellproliferation.Examplesofisoprenoidsarealpha-limonene(foundincitrusoils),geraniol,carvone,andmenthol.Richsourcesinthedietareherbs,spices,barley,ricebran,olives,wine,eggs,dairyproducts,andcertainessentialoils
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usedinflavoring.Isoprenoidsinanimalexperimentsalsoleadtotheincreasedproductionofagroupofenzymesthatdetoxifymanyenvironmentalpoisons.Isoprenoidsalsoincreasetheliveroutputoftwoenzymesconcernedinantioxidantdefenses.Thus,isoprenoidshaveindirectantioxidantproperties.Notallbeneficialagentsinfruitandvegetablesareantioxidants.Ifyoudecidetorelyonantioxidantsupplementsratherthanincreasingthefruitsandvegetablesinyourdiet,youwillbedeprivingyourselfoftheaddedprotectionofferedbyisoprenoids(andprobablyotherasyetunknownchemicals)againstcancerandmanyenvironmentalpoisons.Itistobehopedthatsomeisoprenoidsmaybeaddedtoantioxidantsupplements.
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part2theroleofoxidativestressandantioxidantsinhealthand
diseaseInpart1wesawhowthenormalchemistryofoxygeninevitablyleadstotheproductioninthebodyofreactiveinevitablyleadstotheproductioninthebodyofreactiveoxygenspecies,whichplayanormalroleinimportantbodilyfunctions.However,theseagentsarepotentiallytoxic,andevolutionhasprovidedthebodywithaseriesofbiochemicaldefensesagainstthem.Inmanydiseasesthedelicatebalancebetweenreactiveoxygenspeciesandantioxidantsisdisturbed.Ifreactiveoxygenspeciesareproducedataratehigherthanwhattheantioxidantdefensescancopewith,oxidativestressresults,whichmayleadtotissuedamageanddisease.Medicalscienceisexploringthepossibilityofusingantioxidantsinthepreventionandcureofdisease.
Themegavitaminconceptwasonceregardedwithgreatsuspicionbypractitionersofmainstreammedicine.AccordingtoRuckerandStites,writingin1994,"adecadeago,itwasconsideredhighlyspeculativetoproposeapproachestodiseasepreventionthatinvolvedsupplementation.Nutritionparadigmsimportanttovitaminfunction,however,havenowshiftedtoincludemorefocusondiseasepreventionandconsideration
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ofsupplements.''[182].AsVoelkerputitinaneditorialintheJournaloftheAmericanMedicalAssociation,theflagshipofthemedicalestablishment,inthesameyear[222]:"Thestewofdatadescribingantioxidants'diseasepreventionpotentialiscomingtoaboil....[O]nethingiscertain,vitaminandmineralsupplementshaveenteredtheranksofbonafidescience."Beforewediscussindividualdiseasesinthecontextofthesenewdevelopments,wefirstlookatthemethodsusedbyscientiststostudytheroleofoxidativestressandantioxidanttherapyinthosediseases.
howdowestudytheeffectsofantioxidantsInhumandisease?Therearetwotypesofepidemiologicalstudies,calledtheretroactiveandtheprospective.Athirdtypeofstudy,andoftenthemostinstructive,isthedouble-blind,placebo-controlledmethod.
Intheretroactiveepidemiologicalmethod,researchersselectfromthegeneralpopulationarepresentativesampleof,say,tenthousandpeople.Theyapplycertaincriteriatoeliminatesubjectswhohaveconditionsthatmightcomplicatetheissue(illness,longevity,alcoholism,andsoon).Theythenobtainadietaryhistory,inwhicheachsubjecttriestorememberwhatsortoffoodheorshehaseatenoveragivennumberofyears.Ifthefocusofstudyis,forexample,theantioxidantsvitaminsCandEandbetacarotene,researchersthenestimatehowmuchofthesevitaminsthereporteddietwouldcontain.Theypartitionthesampleintoseveralgroups,takingdatafromthosewiththehighestlevelofintake(usuallytheupperfifth)andthosewiththelowest(usuallythelowestfifth).Researchersthenascertainthenumberofcasesoftheparticulardiseaseunderstudythathaveoccurredineachgroupatthetwoextremes,thehighestfifthandthe
lowestfifth.TheresultsmayshowthatthediseaseoccurslessofteninthegroupwithhighestvitaminEintakethaninthatwithlowestintake.ThiswouldappeartoindicatethatvitaminEprotectsagainstgettingthatdisease.
However,thismethodhasdrawbacks.First,itisdifficultformostpeopletoremembertheirdietovermanyyears.People'smemoriesaboutsuch
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mattersarenotoriouslyunreliable.Furthermore,experimentshaveshownthat,whenpeoplefilloutquestionnaires,theyoftenunwittinglyoverestimatetheirconsumptionoffruitsandvegetables.Theseconddrawbackisthe"uncontrolledvariable"problem.SubjectswithahighintakeofvitaminEmayalsohaveahealthierlifestyle-whichconsistsofengaginginmoreexercise,eatinglessfatanddrinkinglessalcohol,beingsubjecttolessstress,andsoon-thanthosewithalowintakeofvitaminE.Itmaybepreciselythatcombinationofalow-fatdiet,moreexercise,andlessstressthataccountsforthelowerdiseaserate,ratherthantheamountofvitaminEinthediet.Althoughatrialcanbedesignedtocontrolforobviousfactorssuchasalcoholandtobaccouse,thereisalwaysthepossibilityofsomeotherfactorthatresearchershadnotthoughtofbeingthemoresignificantreasonforthedifferenceindiseaseratesbetweentwogroups.
Prospectiveepidemiologicalstudiesalsooperateonaselectedpopulationofsubjects,butthistimeresearchersfollowthosesubjectsforanumberofyears,measuringtheirantioxidantintakeandsometimestheirantioxidantbloodlevels.Attheendofasetperiodoftime,researchersascertainhowmanymembersofthehighestandlowestintakegroupsoftheantioxidantunderstudyhavedevelopedaparticulardisease.Theadvantageofthismethodisthattheresearchersgetmoreaccuratereadingsofeachindividual'santioxidantintakelevelsanddonothavetodependonunreliablememories.Thedisadvantagesarethecostandthelongtimerequiredtocompletetheexperiment.Thismethodalsosuffersfromtheuncontrolledvariableprobleminthatonecannevereliminatetheeffectonthefinalresultsofabetterlifestyleandotherfactorsnotidentifiedwhentheexperimentwasdesigned.
Thebestwayofobtaininginformationisadouble-blind,placebo-controlledstudy,ofwhichtherearetwotypes,preventativeandtherapeutic.
Inapreventativestudyresearchersselectanumberofapparentlyhealthysubjectsusingcertainexclusioncriteria(e.g.,beloworaboveacertainagerange,thepresenceofotherillnesses,andsoon)anddividethemintotwoequalgroups,thetreatmentgroupandtheplacebogroup,matchedforage,sex,andanyotherfactorthatmightbesignificant.Ifallthesubjectsinthetreatmentgroupwereolderpeopleandallthesubjectsintheplacebogroupwereyounger,thenitcouldneverbeprovedthatanyapparenteffectofthetreatmentbeingtestedisnotsimply
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attributabletotheagedifferencebetweenthegroups.Oncethematchedgroupsareselected,thetreatmentgroupisgiventheantioxidanttobetestedandtheplacebogroupaplacebopillthatlooksandtastesthesameastheantioxidant;thesubjectsdonotknowwhichonetheyaretaking.Infact,nooneknowswhichtreatmentanindividualreceivesexceptforonememberoftheresearchteam.Theothermembersoftheteamthatperformtheclinicalevaluationsdonotknowthetreatmentgroupassignments.Neithertheevaluatornorthesubjectareintheknow-hencetheterm"double-blind."Thisexperimentaldesignensuresthatevaluationsarenotsubjecttobias.Attheendofthetrial,itisdeterminedhowmanysubjectsineachgroupdevelopthediseaseunderstudy(e.g.,heartdisease,cancer,orcataract)andhowmanyhavediedfromit.Ofcourse,thetrialcaninvestigatemorethanonedisease.
Atherapeutictrialentailsthesameprocedures,butthesubjectsalreadyhavethediseaseinquestion;thestudyisdirectedtowardfindingoutifthetreatmentimprovestheircondition,oratleastslowsdowntheprogressofthedisease.Theadvantageofthismethodisthelikelihoodthatanyresultsare,infact,attributabletothetreatmentandnottosomeotherfactor.Thedisadvantage,inthecaseofantioxidants,isthattheseagentshavealong-termcourseofaction.Thus,toberelevant,atherapeutictrialmustlastforyearsratherthanformonths.Clearly,ifadiseaseconditiontakestenyearstoestablishitself,thenaclinicaltriallastingonlyoneyearwillnotyieldanymeaningfulresult.Butlong-termtrialsareexpensiveandaburdenonboththeinvestigatorsandthepatients.Itisdifficulttofindsubjectswillingtowaitforyearsbeforetheycanbetoldwhattheyaretaking.Also,inaprotractedtrialitbecomeseasierforthedouble-blindstatustobecompromised-thatis,forsomeonetodiscoverinadvertentlywhichpilliswhich.
Onethingweknowaboutantioxidantsisthattheyaremorelikelyto
helppreventvariousdiseasesthantocurethemoncetheyhavestarted.Inaprotractedillness,suchasParkinson'sdisease,antioxidanttherapyismorelikelytobeeffectiveifitisstartedbeforetheaffectednervecellsinthebrainaredestroyed.However,suchtimingisdifficulttoachieveasthesecellsbegintodiefiveyearsbeforethefirstclinicalsymptomsofthediseasearemanifest.SincethereisnoexistingtesttotellwhichpeoplewilldevelopParkinson'sdisease,meaningfultherapeutic
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trialstostudytherelationshipbetweenantioxidantsandParkinson'sdiseasecannotbecarriedout.Afurtherproblemisthatmanyofthestudiesunderconsiderationinthisbooktestonlyone,orperhapstwo,antioxidants.Thisisapoorstrategy,becauseantioxidantsworktogetherasasynergisticteam.Astudyusinglargeamountsofjustoneantioxidantmayseriouslydisruptthissynergisticprocessandleadtounreliable,orevenundesirable,resultsasisdetailedlater.
Afinaldrawbacktotherapeutictrialsisthat,eveninadiseaseknowntobecausedinpartbyreactiveoxygenspecies,givingantioxidantsbymouthorbyinjectiondoesnotguaranteethattheywillevergettotheplaceatwhichtheyareneeded.Thebodyisnotasackfilledwithfluidinwhichmedicinessimplydiffuseeverywhere.Rather,thebodyhashighlyspecificmechanisms,calledpumps,thattightlycontroltheuptakeoftheantioxidantfromthegutintotheblood,fromthebloodintothetargetorgan,andonceintheorganontotherightplaceintherightpopulationofcells.Forexample,vitaminCissolubleinwater,butnotinfat.Therefore,itcouldnevergetinsidethefattycellmembranewherefatoxidationtakesplace.Ontheotherhand,vitaminEissolubleinfat,andsocanreachthesetargets.Tocircumventthisproblemsomepharmaceuticalcompaniesarebusytryingtomakefat-solublederivativesofvitaminC.Buteventhesewillnotsolveeveryproblem.Wherethecellulartargetisinawaterysurround,evenifsurroundedbyalipid(fat)barrier,water-solublevitaminCwillstillbeneeded.
measurementofoxidativestressIntheclinicBecausemostreactiveoxygenspeciesarehighlyreactivemolecules,theydonottravelfarfromwheretheyaremadebeforeattackingsome
biologicalmoleculesuchasfat,protein,orDNA.Oncethesereactiveoxygenspeciesgetattachedtothebiologicalmolecule,itisnolongerpossibletodetectthemwithoutremovingthebiologicalmoleculefromthebodyandanalyzingitfortracesoftheattachedreactiveoxygenspecies.Asitisnotpracticaltomeasurefreereactiveoxygenspeciesinbloodorbodytissuesinaclinicalsetting,indirectmethodsarenecessary.
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1.Underoxidativestressthemetabolismofthecellchangestoproducecertainstablesubstances.Thesecanbemeasuredinthebreathorinthebloodtodeterminethedegreeofongoingoxidativestress.Examplesarepentane,MDA(malonyldialdehyde),conjugateddienes,andlipidperoxides.Furthermore,oxidativeattackchangesthechemicalstructureofDNA,fat,andproteins.Thesechangescanbedetectedandmeasuredinthelaboratory.Examplesare8-OH¬GonDNA,conjugateddienesandMDA/TBAadductsonfats,andcarbonylsonproteins.
2.Duringoxidativestressthesmall-moleculeantioxidants,suchasvitaminsCandE,whenmoppinguptheexcessreactiveoxygenspecies,tendtobeusedupataratefasterthantheantioxidantscanbemobilizedandrushedtothesceneofaction.Thismeansthatthebloodlevelsoftheseantioxidants,especiallyofvitaminsCandEandbetacarotene,willtendtofallaslongasthedegreeofoxidativestressisgreaterthanthecapacityofthebodytomobilizeenoughantioxidantdefensestodealwiththesituation.Thebloodlevelsoftheseantioxidantscanbemeasured,thusindicatinghowthebattleisgoing.
3.Antioxidantenzymesaresynthesizedwhentheyareneeded.Forexample,underoxidativestress,levelsofSOD,CAT,andGSHpxtendtoriseinthebloodandbodytissues.Thisisbecausereactiveoxygenspeciesactdirectlyonthenucleusofthecell(viathetranscriptionfactorNF-KBmentionedearlier)tostartthesynthesisoftheseenzymes.Thus,thelocalandgeneralantioxidantdefenseswillbeincreased.However,insomecases,thediseaseprocessmaybeduetolowlevelsofoneormoreoftheseenzymesbecausesomethinghasgonewrongwiththecellularmachinerymakingthem-inwhichcasebloodlevelswillbelow,notelevated.
theroleofoxidativestressindiseaseOxidativestress-damageresultingfromanexcessiveproductionofreactiveoxygenspeciesand/orafailureoftheantioxidantdefenses-playsanimportantroleinmanydiseases.Logically,then,antioxidantscouldpotentiallyplayausefulroleintherapy.Duringtheinitialstageofoxidativestressthebody'sdefensesaremobilizedand
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levelsinthebloodandtissuesofantioxidantcompoundstendtorise.Ashasbeennoted,thisisinpartduetothefactthatreactiveoxygenspeciesdirectlystimulatethecelltomakemoreantioxidantenzymes.Iftheoxidativestressistooprolongedortoosevere,theantioxidantdefensestendtobeoverwhelmedbecausethesmallmoleculeslikevitaminsCandEsimplygetusedupandtheirbloodlevelsdecrease.Overwhelmingoxidativestressmayalsocausethereactiveoxygenspeciestoattacktheantioxidantenzymesthemselves-which,asproteins,arevulnerabletosuchanattack-andsodiminishtheireffectiveness.Asavailableantioxidantsareconsumedwithoutreplenishment,withcontinuedoxidativestressandthebuildupofreactiveoxygenspeciesmolecules,cellulardamagecanoccur,leadingtothedevelopmentofdisease.
Thissectiondescribesthosediseasesthoughttobeassociatedwithoxidativestress;itincludesanaccountoftheresultsoftreatmentofthesediseaseswithantioxidants.Itshouldbeemphasizedthatthetechnicalterm"oxidativestress"isnotthesamethingas"stress,"ascommonlyusedtodenotepsychologicalorlifestress.Butthetermdoesconveythesenseofthecontinualbattleinalllivingcellsbetweenpotentiallylethalreactiveoxygenspeciesandtheantioxidantdefenses.
Theorderinwhichthefirsttwelvediseasesispresentedcorrespondstoboththedegreeoftheirimpactonthepopulationatlargeandthedegreeofimportanceofoxidativestressintheiretiology.Therestaregiveninalphabeticalorder.
HEARTDISEASE
CoronaryarterydiseasecausesheartattacksandisthesinglemajorcauseofdeathintheUnitedStates.Itiscausedbytheslowbuildupofaformoforganizedbloodclot(calledanatheromatousplaque)inthe
wallsofthearteriesthatsupplytheheartwithblood.Manyfactorscombinetocausetheseplaques,includinggenes,excessanimalfatsandcholesterolinthediet,excesslow-densitylipoprotein(LDL,thebadformofcholesterol)intheblood,lackofexercise,smoking,andobesity.Butonemajorfactorrelatedtotheothersistheoxidationoffatsintheblood.Asaresultofthisoxidationthefatsintheblood(andelsewhereinthebody)become,sotospeak,rancid.WhatimplicatesLDL
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cholesterolincoronaryheartdiseaseisthefactthatitismoreeasilyoxidizedthanarenormalfats.Oxidizedfatssticktothewallsofarteriesandarethentakenupbycertainwhitebloodcellscalledmacrophages(Greekfor"bigeater").Typically,whenthesemacrophagestakeupanormal(non-LDL)fat,theybecome"full"andstopconsumingfat.Theythenmoveofftoallowanothermacrophagetotakeover.InthecaseofoxidizedLDLfats,thisprocessisaltered.WhenthemacrophagestakeupanoxidizedLDLfat,theswitch-offmechanismthatsignalsfullnessfailstowork;thecellsgoontakingupoxidizedfatandbecomeoverloadedandbloatedwithfattoform"foamycells."Thesefoamymacrophagesceasetooperateproperlyandremaininthearterywalltohelpformtheorganizedclot.Whentheclotblocksthenormalflowofblood,aheartattackislikelytoresult.
Itisnotonlythefailureofnormalmacrophageregulationthatleadstocoronaryheartdisease.Increased"stickiness"ofthewhitecellsandplateletsinthebloodisalsoinvolved.Thefattydepositsinthewallofthebloodvesselscausewhitebloodcells(includingfoamymacrophages)andplateletstosticktothem,whichstartstheprocessofclotformation.Anythingthatincreasesthisstickinesswillbeariskfactorforheartattack.However,ifthesebloodcellsarenotstickyenough,theywillfailtorepairsmalltearsinthevesselwallandhemorrhagemayresult.Aswithanyregulatedprocess,toomuchortoolittlestickinesscanleadtohealthproblems.VitaminEhasbeenshowntoreducestickiness,especiallyinthecaseofbloodplatelets,byamechanismindependentofitsantioxidantproperty.ItalsoprotectsLDLfatsagainstoxidativeattackbyitsantioxidantproperty.
Aheartattackitselfcausesprofoundoxidativestress,withreleaseofreactiveoxygenspeciesespeciallyduringthereperfusionstage,whenthebloodflowisreturningtothedamagedheartmuscle.Chandrasekaretal.haveshownthat,duringthereperfusionstage,the
levelsofmessengerRNAsforproinflammatorycytokinesintheheartareraised[32].Thiselevationmeansthatasignalwassenttothecellnucleustomanufacturemorecytokines(whichareproteins)bymeansoftheDNA-to-RNAsystemofproteinsynthesis,ofwhichmessengerRNAsareapart.Thepurposeofthiscytokineproductionissomewhatobscure,asproinflammatorycytokinesonlymakethingsworsebyincreasingtheblockageofthecoronaryartery.Atthesametimetheresearchshowsthatasignalwassent
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tothenucleusoftheheartmusclecelltomanufacturemoreofthekeyantioxidantenzymesCAT,SOD,andGSHpx(seepart1)soastoprotecttheheartmusclebycounteractingthedeleteriouseffectsofreactiveoxygenspecies.
Ifoxidationoffatsisoneoftheculprits,thenantioxidantsmaybepartoftheremedy.Ifantioxidantscouldslowdowntheoxidationofthefatsthatstartthispathologicalprocess,theymighthelppreventheartattacks.However,tobeeffectivetheseantioxidantswouldhavetobefatsoluble(seepart1)soastobeabletopenetratetowherethedamageisinthefat.
ManyexperimentsinanimalsandinthetesttubehaveshownthatvitaminEwillprotectcellsandfatsagainstfatoxidationinducedbyreactiveoxygenspecies.Heartmuscleisparticularlyvulnerabletooxidativestressbecauseofitsheavyworkloadanditsnormallowlevelofantioxidantdefenses[180].Soitislikelytobeadverselyaffectedbyanyinterferencewithitsbloodsupply,asinaheartattack.Inthecaseofanyorganthattemporarilylosesitsbloodsupply,muchofthedamageisdonebyreactiveoxygenspeciesduringthereperfusionperiod,whenthebloodisenteringtheorganagain.
CLINICALDATAANDMAJORRESEARCHSTUDIES.
Alookattheclinicaldatainhumansandareviewofthemajorresearchstudieswillhelpustounderstandwhetherantioxidantscanpreventoralleviatecoronaryheartdisease,whichIhenceforthterm"heartdisease"withtheunderstandingthatthisincludesonlycoronaryheartdiseaseandnotconditionslikeheartfailureorirregularitiesoftheheartbeat.Thedatafromthethirty-fourmostprominentstudiesontherelationshipbetweenantioxidantsandheartdiseaseispresented.Thesestudiesarenumberedforeaseofreference;thereadercanfollowtheanalysisofhowthesestudiesrelatetoeachother.Youwillnotethattherearedisagreementsinthesereportsbetweenthe
authoritieswhocarriedouttheresearches,andyoumaywonderwhy.Afterall,itdidnottakelongtodiscoverthatpenicilliniseffective.However,inthecaseofthesechronicandcomplicateddiseases,arrivingatfirmconclusionsismoredifficult.Reliablejudgmentsmustbebasedonalltheresearchworkthathasbeencarriedoutandontherecommendationsmadebyalltheexpertsinthefield.
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Inthefirsteightstudiestheinvestigatorsexaminedtherelationshipbetweenthelevelofingestionofantioxidantvitaminsandtheincidenceofheartdisease.
(1)IntheNurse'sHealthStudy,StampferandRimmmeasuredtheintakeofvitaminsCandEandbeta-carotenein87,245Americanfemalenursesoveranaverageperiodofeightyears-atrulyformidableundertaking[207].Theydividedthegroupintothefifthpart(quintile)withthehighestintakeandthefifthpartwiththelowestintake.TheaveragelevelofvitaminEtakenbythehighestquintilewas208mgperdayandtheaverageleveltakenbythelowestquintilewas2.8mgperday.TheyfoundthatthehigherlevelofintakeofvitaminEwasassociatedwitha34percentreductioninheartdisease.Ahigherconsumptionofbeta-carotenewasassociatedwitha22percentdecrease.Iftheintakeofboththeseantioxidantswashightherewasa50percentreduction.VitaminCsupplementshadnoeffect.TheyalsonotedthatvitaminEwaseffectiveonlyifitwasgivenasavitaminEsupplementandnotasmerelyoneingredientinamultivitaminpill.TheyexplainedthisonthebasisofthefactthatvitaminEsupplementstypicallycontainmorethan1oomgperdaywhereasthemultivitaminpillscontainonly30mgperdayorless.Thisisevidencethatthecurrentrecommendeddailyallowance(RDA)forvitaminEmaybetoosmalltoplayaroleinpreventingheartdisease.
(2)Thesameteamthenlookedatapopulationof39,910menoverafouryearfollow-upperiodusingthesamemethods[176].ThemedianintakeofvitaminEinthecaseofthehighestquintilewas419mgperdayandinthecaseofthelowestquintileitwas6.4mgperday.AgaintheyfoundthatthehigherlevelofvitaminEintakewasassociatedwithasignificantreductionintherateofdevelopmentofheartdisease;vitaminChadnoeffect.Inthisstudybeta-carotenewasalsoeffectivebutonlyinsmokers.Thisfindingwithbeta-carotenemighthavebeenduetotheshortertermofthisstudyascomparedwiththeir
firststudy.Thissuggeststhatthetherapeuticeffectsofbeta-carotenemaytakealongperiodoftimetodevelop.Theremayalsobeagenderdifferenceinvolved,sincethisstudyinvolvedonlymenwhereasthepreviousstudyinvolvedonlywomen.Theauthorspointout
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thatthe"healthierlifestyle"explanationfortheseresultswasunlikelytoberight,asthesubjectswhotookhighlevelsofvitaminCsupplementshadequallyhealthylifestylesasthosewhotookhighlevelsofvitaminEsupplements,butobtainednobenefit.Inalaterpaperthesameauthorsstatethatatleast100mgperdayofvitaminEintakeisrequiredtoproduceaneffectinloweringtherateofheartdisease[207].
(3)Thethirdstudywascarriedoutonapopulationof34,486postmenopausalwomenwhowerefreefromheartdiseaseatthestartofthetrial[114].Theinvestigatorsmeasuredtheintakeofantioxidantvitaminsandfoundthat,ifvitaminEwasobtainedfromfood(mainlyfromnuts,seeds,margarine,andmayonnaise),therewasastrongprotectiveeffectagainstheartdisease.Therewasnoprotectiveeffectifthevitaminwastakenasamultivitaminsupplement.TheauthorsexplainedthisresultalsoasowingtothefactthatthedoseofvitaminEinthemultivitaminsupplementsusedbythesesubjectswastoolow.Again,vitaminChadnoeffect.
(4)ThePhysician'sHealthStudyisanothermajorstudy,thistimeconfinedtobeta-carotene.Fortwelveyears,27,071Americanmalephysicianseachreceivedasmalldoseofbeta-carotene(equivalenttotwocarrotsperday)[82].Theinvestigatorsreportednobenefitforpreventingheartdiseasefromthislevelofbeta-caroteneintake.
(5)AsimilarstudycarriedoutinBasel,Switzerland,foundthateightyearsofbeta-caroteneintakeshowednoclinicalbenefit;butifthelengthofthestudywasincreasedtotwelveyears,therewasasignificantreductionintheincidenceofheartdisease[66].Theresearchersstressheartdisease'sslowrateofdevelopmentand,ifoneistogetatrueestimateontheeffectivenessofanyprocedure,theneedforlongtrialsratherthanshortones.
(6)IntheScottishHeartHealthStudyitwasfoundthatahighlevelofintakeofvitaminsEandCandbeta-caroteneappearedtoprotectmen,
butnotwomen,againstheartdisease[216].Thisstudyusedasophisticatedstatisticalmethod(multivariantdiscriminantanalysis)foranalyzingtheresults;theactuallevelsofvitaminEintakeinvolvedarenotmentioned.
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(7)TheLipidResearchClinics-CoronaryPrimaryPreventionTrialstudied1,899menaged40to59andmeasuredtotalcarotenoids(notjustbeta-carotene,whichcontributesonly25percentofthetotalcarotenoidintakeofthediet)[146].Theresultsshowedastrongprotectionagainstheartdiseaseformenwhohadneversmoked.Theauthorsalsostressthatthedurationofsuchstudiesmustbeatleasttenyearsforvalidconclusionstobedrawn.
(8)Oneofthelongestlongitudinaltrialseverconductedstudied1,556menoveraperiodoftwenty-fouryears[158].Theresultsshowedthathighlevelsofintakeofbeta-caroteneandvitaminCledtoa20-30percentdecreaseinthedeathratefrombothheartdiseaseandcancer.
Instudies9to13,theresearchersinvestigatedtherelationshipbetweenbloodlevelsofantioxidantvitaminsandtheincidenceofheartdisease.
(9)GeyhasreportedtheresultsoftheMONICAprojectcarriedoutbytheWorldHealthOrganization[65].ThisprojectstudiedtherelationshipbetweenbloodlevelsofvitaminEanddeathratesfromheartdiseaseinsixteenEuropeancountriesandfoundthatvitaminEhadastronglyprotectiveeffect.Whengiveninsufficientamounts,vitaminEworkedbetterincombinationwithseveralantioxidant''helpers"thanonitsown.Aswehaveseen,antioxidants(particularlyvitaminsB3ornicotinamide,E,andC)worktogetherasateamandneedtobegivenasateam,insufficientquantities,tobemosteffective.MostmultivitamintabletformulationscontaininsufficientamountsofvitaminE.
(10)Riemersmaetal.measuredbloodlevelsofvitaminsEandCinapparentlyhealthymiddle-agedmeninfourlocations-twoinFinland,oneinScotland,andoneinsouthernItaly[174].Inthefirstthreelocationsthereisaveryhighincidenceofheartdisease;insouthernItalyheartdiseaseislessprevalent.BloodlevelsofvitaminsCandE
werelowinScotlandandinoneoftheFinlandlocationsandhighinItaly.ItalianstypicallyeatanymorefreshfruitsandvegetablesthandoScotsandFinns.ButinKarelia,theotherFinlandlocation,vitaminClevelswerenotlow,yettherateofheartdiseasewas
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high.TheauthorssuggestthatthisapparentdiscrepancymightbeduetothefactthattheKarelianswereingeneralmoreobeseandhadhigherbloodpressurethandidtheotherthreegroups-bothfactorsthatpredisposetoheartdisease.Indeed,dietarystudiesshowthatFinnshavethehighestintakeoffatinEurope.Thisagainillustratestheimportantpointthatotherfactors(suchasbloodpressureandobesity)maycomplicatetheinterpretationoftheeffectsofantioxidants.
(11)Anotherstudycomparedtwogroupsofyoungpeople,onefromNaples,Italy,andtheotherfromBristol,England[161].TheItalianshadhigherbloodlevelsofvitaminEandmuchhigherlevelsofbetacarotene.Althoughthegroupsatethesamequantityofvegetables,theItaliansconsumedconsiderablymoretomatoesandoliveoil.TheItalianshadmuchlowerratesoffatoxidation(asmeasuredbyplasmalevelsofconjugateddienesandlipidperoxides,whichareproductsoflipidoxidation).Tomatoes,whichcontaintheimportantantioxidantlycopene,andoliveoil,whichalsocontainsmanyantioxidants,arekeyingredientsoftheMediterraneandiet,whichmanystudieshaveshownofferspowerfulprotectionagainstheartdiseaseandsomeformsofcancer.
(12)Singhetal.studiedimpoverishedindustrialworkerswhoateapoordietandhadhighexposuretotoxicfumesderivedfromdieselenginesandheavymetalssuchascopperandlead[196].ThosesubjectswhodevelopedheartdiseasehadlowerbloodlevelsofvitaminsEandCandofbetacarotenethandidthosewhodidnotdevelopheartdisease.
(13)Middle-agedmeninLithuaniahavefourtimesasmanyheartattacksasmiddle-agedmeninSweden.Tofindoutwhy,Kristensenetal.studiedonehundredpeople,fiftyfromeachcountry[111].Therewerenodifferencesbetweenthetwogroupsintheordinaryriskfactorssuchasbloodcholesterol,smoking,obesity,andhighbloodpressure.Butthereweretwosignificantdifferences:theLithuanians
hadlowdensitylipoproteins(badcholesterol)thatweremoreeasilyoxidized,andtheyhadlowerbloodlevelsofsomeantioxidants,suchasbetacarotene,lycopene,and,interestingly,gamma-tocopherol(arelativeofvitaminE).Levelsofalpha-tocopherol(vitaminE)werethesame.Theinvestigatorssuggestedthattheirresultsmightbeduetothefact
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thatLithuaniansingestedmorepolyunsaturatedfatsbutconcludedthattheirantioxidantstatuswasalsoimportant.TheauthorsquoteanotherSwedishstudythatshowedthatmenwithcoronaryheartdiseasehadlowbloodlevelsofgammatocopherolbutnormallevelsofalpha-tocopherol.Thisunderscorestheimportanceofgammatocopherolinthedietandsuggeststhat,infuture,suchstudiesshouldpayasmuchattentiontogammatocopherolastoitsmorefamousrelativealpha-tocopherol.
Studies14to16concentratedonvitaminCalone.
(14)TheFirstNationalHealthandNutritionExaminationSurvey(NHANES)cohortstudywasbasedonaten-yearfollow-uponthedietof11,348Americanadultsaged25to74[52].TheresultsindicatedthatahighdietaryintakeofvitaminCappearedstronglytoprotectmenagainstdeathfromheartdisease(aswellasdeathfromcanceranddeathfromallcauses);butwomenwereonlyweaklyprotected.However,thisstudyhasbeencriticizedontechnicalgroundsbyHerbert[83].Enstromhasrepliedtothiscriticism[51].
(15)Tooheyetal.studied172AfricanAmericanSeventh-DayAdventists(whosereligiouspracticeprohibitssmokingtobaccoanddrinkingalcohol)[217].TheresultsshowedthatahighintakeofvitaminCwasstronglyassociatedwithalowerrateoffatoxidation(probablybecauseofthewayvitaminC"helps"vitaminE,asdescribedinpart1).Theresearchersconcludedthattheirresultswereprobablynotduemerelytoeatingmorefruitsandvegetables,mainlybecausetheyfeltthattheyhadnoteliminatedthepossibilityoftheinfluenceofotherfactors,suchasabetterlifestyle.
(16)Nyyssönenetal.tested1,605menaged42to60inalong-termstudyinFinlandoftheeffectsofvitaminCdeficiency[149].Theapparentlyhealthysubjectsenteredthestudybetween1984and1989andwerefollowedupuntil1996.Someninetysubjectshadabloodlevellowerthanthecutoffpointthatindicatesadeficiencystateof2
mg/L.ThesesubjectsshowedahighlysignificantincreaseinthenumberofheartattackswhencomparedwiththerestofthesubjectswhohadnormalbloodlevelsofvitaminC.Thiswassoevenallowingforotherfactorssuchastheamountofsaturatedfats,carotene,
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fiber,andteaconsumed.However,furtherincreasesinthebloodlevelofvitaminCabovethelimitof2mg/Lconferrednofurtherprotection.ThissuggeststhatvitaminCsupplementsbythemselveswouldnothavebeenofhelp.However,itisamatterofconcernthatsomanyFinnsweredeficientinvitaminC.PhysiciansshouldbearinmindthepossibilityofapreviouslyundetectedvitaminCdeficiencywhenevaluatingasubject'sriskofhavingaheartattack.
Theprotectiveeffectofantioxidantswasestimatedinstudies11and15bymeasuringthelevelsoffatoxidationthatpredisposestowardheartattacks;intheotherstudiesitwasestimatedbymonitoringthedevelopmentofheartdiseaseitself.Wecansumuptheforegoingreviewofthemajorepidemiologicalstudiesasfollows.
INTAKESTUDIES
HighdietarylevelsofvitaminEaloneprotectedagainstthedevelopmentofheartdiseaseinthreestudies(1,2,and3).Therewerenostudieswithnegativeresults.
VitaminCwasprotectiveorpartlyprotectiveintwostudies(14and15)buthadnoeffectinthreestudies(1,2,and3).ItsmaineffectivenessmaybeinpeoplewhohaveanactualvitaminCdeficiencystate.
Beta-carotenewasprotectiveinstudy5butnotinstudy4.
ThecombinationofvitaminsEandCandbeta-carotenewasprotectiveinstudy6.
Totalcarotenoidswereprotectiveinstudy7.
Thecombinationofbeta-caroteneandvitaminCwasprotectiveinstudy8.
VitaminCwasprotectiveinvitaminCdeficientindividualsinstudy16.
Intwostudies(6,14)menwerereportedtohaveamorefavorableclinicalcoursethanwomen.
BLOODLEVELSTUDIES
HighbloodlevelofvitaminEalonewasprotectiveinstudy9.
HighbloodlevelsofvitaminsEandCwereprotectiveinstudy1o.
HighbloodlevelsofvitaminEandbeta-carotenewereprotectiveinstudy11.
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LowlevelsofvitaminE,vitaminC,andbetacarotenewereariskfactorinstudy12.
Lowlevelsofbetacarotene,lycopene,andgamma-tocopherolconstitutedariskfactorinstudy13.
Collectively,thisepidemiologicaldatastronglysupportsaprotectiveroleforvitaminEinthepreventionofcoronaryheartdisease,ifgivenatanadequatedose(over1oomgperday).ItisbettertoadministervitaminEtogetherwithitssupportiveantioxidants.Theevidenceforbetacarotene'sroleisweaker,buttotalcarotenesappeartobemoreeffectivethanbetacarotenebyitself.TheevidenceforanyprotectiveroleofvitaminCadministeredbyitselfisunconvincing,exceptinpeoplewhohaveanactualvitaminCdeficiency-possiblybecauseheartdiseaseistheresultoffatoxidationandvitaminC,awater-solubleantioxidant,doesnotpenetrateafattyenvironment.However,ifvitaminEisindeedprotective,thenvitaminCmaybeneededinitsroleasahelperofvitaminE.ThuswecanexpectvitaminCtobeusefulwhengiventogetherwithvitaminE,butnotwhengivenbyitself.
FIVEDOUBLE-BLIND,PLACEBO-CONTROLLEDSTUDIES
(17)Stephensetal.haverecentlyreportedoneofthefirstresultsofsuchatrial-theCHAOSstudycarriedoutinCambridge,England[200].Therewere2,002subjectswhowerestudiedforanaverageofseventeenmonths.HalfweregivenvitaminE(800mgperday),andtheotherhalfreceivedaplacebocapsule.InthetestgroupbloodlevelsofvitaminErosesubstantially,showingthatitwasbeingabsorbedadequately.TheresultsshowedasignificantfallinthenumberofheartattacksinthegroupthathadbeengiventhevitaminE.Thenumberofdeathsdidnotdecrease,buttheinvestigatorsnotedthatmostoftheseoccurredatthebeginningofthetrial,sothevitaminEmightnothavehadtimetowork.Otherstudieshavedemonstrated
thatbenefitsfromadministrationofvitaminEneedtimetodevelop.
(18)Anotherdouble-blindstudyshowedthatvitaminE(400mgperday)wasprotectiveagainstheartattacks[208].Theprotectionwasincreasedinthecaseofthosesubjectswhoalsotookaspirin(325mg)daily.
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(19)TheAlpha-tocopherol-beta-carotene(ATBC)study,whichwasprimarilyaninvestigationofcancer[5],alsoreportedontheincidenceofheartattacksamongthesubjects[170].Thestudyinvolved1,862malesmokersinsouthernFinland;eachhadhadoneheartattack.Thesubjectsweredividedintofourgroups.GroupAreceived50mgperdayofvitaminE;groupBreceived20mgperdayofbeta-carotene;groupCreceivedboth;andgroupDreceivedneither.AfterfiveyearsthesubjectsingroupA,whohadtakenonlyvitaminE,hadnodifferenceinfatalheartattacksascomparedwiththecontrolgroupD,butshoweda38percentreductioninnonfatalheartattacks.Butbothgroupswhoweregivenbeta-caroteneshowedsignificantincreasesinfatalheartattacks.InaneditorialintheissueoftheLancet[209]thatreportedtheresults,Stephens,amemberoftheCHAOSteam,pointedoutthattheATBCstudyusedonlyone-tenththedoseofvitaminEthattheCHAOSstudyhadused;moreover,theATBCinvestigatorshadusedsyntheticvitaminEwhereastheCHAOSgrouphadusednaturalvitaminE,whichischemicallydifferent(aswesawinpart1).StephensconcludedthatthebulkoftheevidencesupportstheuseofvitaminE,butnotbeta-carotene,totreatcoronaryheartdisease.Furthermore,instudy1oreportedabove,thesouthernFinnshadanaberrantresult,astheyhadhighbloodlevelsofvitaminCbutalsoahighlevelofheartattacks;inotherstudieshighbloodlevelsofvitaminCareassociatedwithalowincidenceofheartattacks.Theconfoundingfactorinthatstudymighthavebeenthesubjects'veryhighconsumptionoffat.Interestinglyenough,anotherstudyofLappslivinginnorthernFinlandshowedthattheyhadverylowlevelsofheartdisease[129]LappshaveaquitedifferentdietfromsouthernFinns'.TheresearchersattributedtheLapps'lowlevelsofheartdiseasetotheirdiet,whichprovidesrichsourcesofvitaminE,albumin,andselenium.
(20)TheEstablishedPopulationforEpidemiologicalStudiesinthe
Elderlyexaminedtheroleofantioxidantsupplementation(vitaminsEandC)inapopulationof11,178peopleaged67to105.SupplementsofvitaminEaloneweresignificantlycorrelatedwithalowermortalityratefromheartattacks[128].
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Asummaryofdouble-blind,placebo-controlledstudiesisasfollows:
VitaminEappearedtoreducethemortalityratefromheartattacksinonestudy(20)butnotintwoothers(17,19).
VitaminEappearedtoreducethenumberofheartattacksinallfourstudies(17-20).
VitaminCwasnottestedbyitself.
Beta-caroteneappearedtoincreasethemortalityfromheartattacksinonestudy(19).
Instudies21-26thesubjectswerepatientsactuallyundergoinganacuteheartattack.
(21)Singhetal.studied109casesofacutemyocardialinfarctionand182controls[197].TheyfoundthattheplasmalevelsofvitaminsA,C,andEandofbeta-carotenefellduringtheattack.Plasmalevelsofoxidizedfatsrose.
(22)Patientsfollowingaheartattackhadasignificantlyhigherdeathrateiftheirbloodtotal-antioxidantcapacity(excludingalbuminanduricacid)waslow[144].
(23)Inarandomized,double-blindcontrolledstudyof125patientswithamyocardialinfarction,63ofwhomweregivenantioxidants(vitaminA50,000internationalunits;vitaminCIG;vitaminE400mg;andbeta-carotene25mg)fortwenty-eightdaysand62ofwhomweregivenplacebo,thepatientswhoreceivedtheantioxidantshadlesssevereheartattacks(smallerinfarctsize,lesspain,improvedheartfunction,andlowerlevelsofoxidizedfatsintheblood)thandidthosewhohadreceivedplacebo[198].
(24)&(25)Chamiecetal.measuredtheeffectsofvitaminE(600mgperday)andvitaminC(600mgperday)ontheelectrocardiogram
(EKG)afteranacuteheartattackinaplacebo-controlledstudy[31].TheyfoundthattheplacebogrouphadanumberofsignsintheEKGtypicalofaheartattack.TheseEKGchangeswerenotseeninthevitamin-treatedgroup.Inasimilarstudyusinganotherantioxidant(N-acetylcysteineorNAC),thepatientsgiventheantioxidantsshowedlessimpairmentofheartfunctionandlessfatoxidationthandidthepatientsgiventheplacebo.
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THEEFFECTOFANTIOXIDANTSONPHYSICALCHANGESINARTERIES
(26)CoronaryangiographyisanX-raymethodoflookingatthearteriesoftheheart.Hodisetal.usedthismethodon56mengivensupplementsofvitaminsCandEaftercoronarybypasssurgery[88].TheresultswerethatinmildandmoderatecasesthevitaminsledtoasignificantslowingdownofthediseaseprocessinthearteriesasshownbytheX-raypictures.However,thiswasnottrueinseverecases.Theslowingdownofdiseasewaslargelyduetotheintakeofover1oomgperdayofvitaminE.
(27)Asimilarinvestigationwascarriedoutonthecarotidarteriesin1,187people[21].Theinvestigatorsusedultrasoundtomeasureinthelivingpersonthedegreetowhichatherosclerosishadblockedtheartery.HighbloodlevelsofvitaminEwereassociatedwithlessarteryblocking.Also,thereweremoresignsoffatoxidationinthebloodinthosepeoplewithlowbloodlevelsofvitaminE,selenium,andbetacarotene.TheinvestigatorsconcludedthattheirresultssupportaprotectiveroleofvitaminEinheartdisease.
Studies24-27yieldimportantfindingsthatprovidehardobjectiveevidenceofthebenefitsofantioxidanttreatmentinheartdisease.Furthermore,thestudiesinthissection(17-27)withoutexceptiondemonstratethatvitaminEatadosageofaround400mgperdayhelpstopreventheartattacksandlessenstheeffectsofanacuteheartattack.Again,vitaminCseemedtohavelittleeffectexceptasahelperofvitaminE.
(28)Patientsonrenaldialysishavefivetimesthenormalrateofheartattacks,possiblybecausethedialysisprocedureremovesthekeyantioxidantsvitaminCanduricacidfromtheblood.Suchpatientsurgentlyneedtoincreasetheirantioxidantintake.
AnimalstudieshaveshownthatvitaminQ10protectstheliningofthebloodvesselsintheheartagainstoxidativeattack[227].SeveralstudieshavefocusedontheantioxidantvitaminQl0inhumans,ofwhichtwoarereviewedhere.
(29)Kuklinskietal.studied61casesofacutemyocardialinfarction(heartattack)foroneyear[113].HalfweregivenvitaminQ10plus500µgselenium,andtheotherhalfplacebo.Intheexperimentalgroup
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noneshowedanyabnormalityoftheEKG,withnodeathsfromheartdisease.Inthecontrolgroupgivenplacebo40percentshowedanabnormalEKG,andthereweresixdeathsfrommyocardialinfarction.Theauthorsadviseantioxidanttreatmentforallcasesatrisk.
(30)AsimilarbutuncontrolledstudyshowedthatvitaminQ10(75-600mgperday)in424cardiacpatients(averagefollow-uptime,7.8months)wascorrelatedwithclinicalandelectrocardiographicalimprovement[116].Theseauthorsciteseveralpreviousdouble-blind,placebocontrolledstudieswhichshowvitaminQ10tobe"safeandeffective."
THEFRENCHPARADOX.
Nutritionalexpertshaverecognizedforyearswhattheycallthe"Frenchparadox."AlthoughtheFrenchhaveadietrichinfats,cholesterol,andallsortsofdeliciousfoodsthataresupposedtobeverybadforyou,theyalsohavealowrateofheartdisease.Somenutritionistshavesuggestedthatthisisbecauseoftheredwinethattheydrink[69,701].(Ofcourse,theyalsoeatadietrichinprotectivefruits,vegetables,herbs,garlic,andoliveoil.)Redwinecontainspowerfulantioxidantflavonoids(inparticularquercetin,rutin,reservatol,andcatechin).Whitewinecontainslesseramounts.Thesechemicalsarealsofoundintea,onions,andapples.However,itispossiblethattheFrenchparadoxmayalsobedueinparttothehigherintakeofvitaminE,especiallyintheformofsunflowerseedoil.
(31)Hertogetal.inZutphen,Holland,studied805menaged65to84forfiveyears[86].Theymeasuredthetotalflavonoidintake,65percentofwhichcamefromtea,13percentfromonions,and10percentfromapples.Theyfoundthatahighflavonoidintakewasassociatedwithalowerdeathratefromallcauses.ThreeotherstudiesreviewedbyHollmanetal.(theNetherlandsCohortStudy,whichinvolved120,850menandwomen,andtwostudiesinFinland,oneof
whichinvolved5,130menandtheotherwomenand550men)allshowedaprotectiveeffectofhighdietaryflavonoidintakeagainstheartdiseasebutnotagainstcancer[91].Ithasbeensuggestedthatifeveryonedranktwoglassesofredwineadaytherateofheartdiseasewouldfallby40percent.Thismaybe
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somewhatofanexaggeration,butcertainlyflavonoidsareimportantinthediet.Allfourstudiesonflavonoidsheredescribedfoundthemtobeprotectiveagainstheartattacks.
(32)Anotherrecentstudy,whichinvolvedresearchersintenEuropeancountries,hasshiftedthefocusofinterestontolycopene(themainantioxidantintomatoes)[110].Insteadoftheusualbloodlevelstheseresearchersmeasuredthelevelofvariousfat-solubleantioxidantsinthebodyfat(adiposetissue).Thisisalogicalplacetolookforcompoundsthataresolubleinfatratherthaninwateryblood.Theyfound,first,thatlycopeneandbetacarotenelevelsinbloodareaboutthesame,butthatfatcontainsmuchmorelycopene.Next,theyfoundthathighfatlevelsoflycopenewereassociatedwithalesserriskofheartattacks.Thiswasnotsoforalpha-orbetacarotene.Theyalsocommentthatlycopeneisamuchbetterantioxidantthanbetacarotene.Itispossible,therefore,thattomatoesaremoreprotectivethancarrots.
(33)Nitroglycerineisadrugthatiscommonlyusedinthetreatmentofangina.Oneofitsdrawbacksisthattolerancedevelopstoitsactionthatis,dosesthatareinitiallyeffectivedonotremainso.Onerandomized,double-blind,placebo-controlledtrialhasfoundthatvitaminEsupplementspreventthedevelopmentofthistolerance[227].TheresearchersthereforerecommendtheuseofvitaminEsupplementsinpatientswhotakenitroglycerine.
(34)AstudycomparingsmokersandnonsmokersreportsthatpeoplewhosmokecigaretteshavelowlevelsofvitaminsCandEbutnormalantioxidantenzymesintheirredbloodcells.Whensmokershaveaheartattack,theirbodiesrespondwithmoreseverechangesinantioxidantstatus(loweredlevelsofantioxidantenzymesSOD,GSHpx,andCAT,andantioxidantvitaminsA,C,E,andGSH)thanthoseofnonsmokers.Theauthorsofthestudyrecommendthat
smokerstakeantioxidantsupplements,inparticularvitaminsCandE.
BLOODPRESSURE.
Finally,therehasbeenonerandomized,double-blind,cross-overstudyoftheeffectofantioxidantsonbloodpressure.Some30percentofadultsintheWestsufferfromelevatedbloodpressure.
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Galleyetal.inScotlandselectedthirty-eightpatientswithhighbloodpressureandseventeenpatientsfromthesameclinicwithnormalbloodpressure[61].Eachpatientreceivedanantioxidantcocktail(orplacebo)foreightweeks,followedbyatwo-weekwashoutperiod,andthenplacebo(orantioxidantcocktail)foranothereightweeks.ThecocktailconsistedofvitaminC(500mgs),vitaminE(600mgs),beta-carotene(30mgs),andzinc(200mgs).Bloodpressurewassignificantlyloweredinbothgroupsofpatients,butmoresointhosewithhighbloodpressure.Thelattergroupalsoshowedanincreaseinurinaryexcretionofnitrite,ametaboliteofnitricoxide.Theresearchershypothesizedthatthebloodpressurewasloweredbecausetheantioxidantsprotectednitricoxide(whichlowersbloodpressurebydilatingbloodvessels)fromoxidationbythesuperoxideion.Sincehighbloodpressurepredisposestoheartdiseaseandstrokes,theresearcherssuggestedthatthisvitamincocktailmightbeeffectiveinreducingtheincidenceofthesediseases.AstudyoftheeffectsofvitaminQl0onhypertensionshowedthatithadapositiveclinicaleffect[117].Bloodpressurelevelwasreducedandtherewaslessneedforantihypertensivedrugs.
thesestudiesprovidestrongevidencethatvitaminEshouldbetakenatadoseofatleast400mgperdaybyanyonewishingtodecreasethelikelihoodofhavingaheartattack.Thisdosecannoteasilybeobtainedfromdietalone,asonewouldendupeatingtoomuchfat.TheevidenceindicatesthatthisdoseofvitaminEissafe,exceptinthecaseofpeoplewithcertainbloodcoagulationdisorders;itmayresultinasmallincreaseintheriskofhemorrhagicstroke,asdetailedinpart3.AlongwiththevitaminEoneshouldalsotakeanadequateamountofitshelperantioxidants.However,beta-carotenebyitselfshouldbeavoided,especiallybypeoplewhohavehadoneheartattack.WhyistheefficacyofthisdoseofvitaminEnotwidelyacceptedbytheauthorities,includingmanyphysiciansandother
healthprofessionals?Giventheevidence,itisrathersurprisingthatmanyexpertsstillmaintainthattheofficialRDAofvitaminEof20mgperday-twentytimessmallerthantheamountneededtoconferaprotectiveeffectagainstheartdisease-issufficienttocoverallourhealthneeds.Themotivationsandimplicationsofthecurrentpolicieswillbeconsideredlater.
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CANCER
Cancerscanoriginateinalmostallthecelltypesinthebody,andthedevelopmentofcancerisanenormouslycomplicatedprocessinwhichmanybiochemicalsystemsplayarole.Prominentamongthesesystemsarethosethatdamagethecell'sDNA.ManyagentscandamageDNA:ultravioletlight,radiation,cancer-producingchemicalssuchastar,andreactiveoxygenspeciesmolecules.Alargenumberofanimalexperimentsshowthatreactiveoxygenspeciescaninducecancersinvarioussystemsandthatantioxidantscanbeprotective.AlmostallcancercellshavelowlevelsoftheantioxidantenzymesCATandGSHpxandhaveanabnormalregulationoftheseenzymes[150].Asaconsequence,theyaremorevulnerabletooxidativestressandfurtherDNAdamagethanarenormalcells.Indeed,thecancercellsthemselvesshowmuchchemicalevidenceofoxidativestress.Withdefectiveantioxidantenzymes,thesecellscannotproperlyhandlehydrogenperoxide(H202),whichprocess,accordingtoresearchers,''offerstremendouspotentialforcancertherapy"[150].Itispossiblethatnewdrugsmaybedevelopedthatcandetoxifythehydrogenperoxide.Moreover,itispossible,butnotyetestablished,thatantioxidantsmayaffectbiochemicalmechanismsotherthandamagetoDNAthatareinvolvedintheformationandgrowthofcancers.Thesemayincludethecomplexmechanismsthatgovernthedifferentiationandgrowthofcells.
Whatisnowrequiredareexperimentsinhumansthatshowwhetherornotantioxidants,eitherinahealthydietrichinfruitsandvegetablesorgivenassupplements,actuallyhelptopreventoralleviatecancerinpeople.
TheWorkStudyGrouponDiet,Nutrition,andCanceroftheAmericanCancerSocietyhasestimatedthataboutone-thirdofthehalf-milliondeathseachyearfromcancerintheUnitedStatesarea
consequenceofdiet[236].Thus,morethan15o,000deathsayearcouldbepreventedbyasimplechangeofdiet,tosaynothingoftheresultingenormousreductioninhealthcosts.TheWorkStudyGrouprecommendsthefollowingstepstolowercancerrates:eatlessbutconsumeamorevarieddiet;eatmorefruits,vegetables,wholegraincereals,legumes,andnuts;lowerfatintake;drinklessalcohol;avoidsmoked,salt-cured,andnitritepreservedfoods;andtakeantioxidantsupplements(especiallyvitaminE)"incertaincases."
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Therehasbeenanenormousvolumeofclinicalresearchintotheroleofdietincancer.Blocketal.attheNationalCancerInstitutereviewed156epidemiologicalstudiesoftherelationshipbetweenadietrichinfruitsandvegetablesandvariousformsofcancer[17].Theyreportedthatformostcancerssuchadietcutsthecancerrateinhalf.Especiallyfavorablesitesarethelung(aftercontrolforsmoking),inwhich24outof25studieshadpositiveresults;esophagus,mouth,andlarynx(24outof25positive);pancreasandstomach(26outof30positive);colon,rectum,andbladder(23outof28positive);andcervix(11outof13positive).Clearly,fruitsandvegetablescontainsomeagentsthatprotectagainstcancer.Blocketal.concludedthatthehealthylifestylehypothesiswasunlikelytoaccountforthedata.Theyalsostressedthegreatimportanceofthehelpingactionofthelargenumberofdifferentantioxidantsinthediet.
TavaniandLaVecchiaoftheMarioNegriInstituteinMilan,Italy,havereviewedalargenumberofstudiesoftheeffectofdietinaMediterraneanpopulationandconcludedthatfruitsandvegetablesofferastrongprotectiveeffect(61-87percent)againstmanyformsofcancer(betterprotectioninthehigherrespiratoryanddigestivetractsthaninthelowertracts),butnoneagainstcancersofthelymphaticsystem[213].Theevidencesuggestedthatrawvegetableswerebetterthancooked,andvegetableswerebetterthanfruit.
Flaggetal.havesummarizedwhattheyconsideredtobealltheadequatelycontrolledandconductedstudiespublishedbetween1985and1992ontherelationshipbetweendietaryintakeandbloodlevelsoftheantioxidantsbeta-caroteneandvitaminsCandE,andvariousformsofcancer[55].Theyestimatedthestrengthoftheprotectionandwhethertherewasaconsistentrelationshipbetweenhigherbloodlevelsoftheantioxidantsandincreasedprotection(calleda"dose/response"relationship).Theresultsindicatedthattheantioxidantsprovidedgoodprotectionagainstcancerofthelungand
upperrespiratoryanddigestivetracts,someprotectionagainstcancerofthecolonandcervix,butnoneagainstbreastandprostatecancer.Itisgenerallythoughtthatbreastandprostatecancersaremainlycausedbyadisturbanceinhormonalcontrol;thus,thelackofprotectionaffordedbyantioxidantsisnotsurprising.However,onestudyof47,894subjectsinBoston,whichmeasuredcarotenoidsinthediet,found
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thatadiethighspecificallyinlycopene(fromtomatoesortomatopaste)seemedtoprotectagainstthedevelopmentofprostatecancerduringthefouryearsofthestudy[67].
Diplockhasalsoreviewedalargenumberofstudiesontherelationofantioxidantdietaryfactorsandcancer[43].Hefoundthatantioxidantswereprotectiveincancersofthelung,upperrespiratoryanddigestivetracts,stomach,bladder,pancreas,cervix,andovary,butnotincancersofthebreastandprostate.Healsoconcludedthatforcolorectalcancersomeingredientofthedietseemstobeimportant,butitmightbefiberratherthanantioxidants.
Somereportsofprospectivestudiesatfirstsightwouldappeartopaintalessoptimisticpicture.A1996issueoftheNewEnglandJournalofMedicinecarriedtwoimportantpapersandaneditorialthathavehadwidespreadrepercussions.ThefirstpaperrelatedtotheCARETstudy(beta-caroteneandRetinolEfficacyTrial)[154].Thiswasafour-yeardouble-blind,placebo-controlledstudyof18,314malesandfemaleswithahighcancerriskfromsmokingorexposuretoasbestos.Thedosageadministeredtosubjectswas30mgofbeta-carotene(equivalenttofourcarrotsaday)plus25,000internationalunitsofretinol(vitaminA).Theresultswerea28percenthigherincidenceinthetreatmentgroupthanintheplacebogroupoflung(butnotother)cancer,17percenthigherincidenceofmortalityfromallcauses,anda28percenthigherincidenceofmortalityfromheartdisease-leadingtoearlyterminationofthestudy.However,theauthorsadmitthattheycouldnottellwhetherthebeta-caroteneorthevitaminA(orthecombination)wastheculprit.Theyconcludedthatitwouldbeunwisetogivelargedosesofonlyonedietaryantioxidantasthismightleadtoaseriousimbalanceoftheimportanthelpingactionoftheotherantioxidants.Thisisquiteplausiblebecauseoftheimportantsynergisticactionoftheantioxidantvitamins.Theauthorsalsocriticizedmanyoftheepidemiologicalstudiesreportinganapparent
protectiveeffectoffruitsandvegetablesinthedietbecausetheyignore,orfailtocontrolproperlyfor,othervariables,suchasthelevelofintakeoffatsandredmeat,exerciselevels,lifestyle,andsoon,thatmightactuallyhavebeenresponsibleforthereportedresults.Manystudieshave,infact,donetheirbesttocontrolforsuchvariables.
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ThesecondpaperreportedonthecurrentstatusofthePhysician'sHealthStudy[82],whichhaslastedfortwelveyearsandhasinvolved27,071Americanmalephysicians(11percentsmokers;35percentformersmokers;54percentnonsmokers)givenasupplementofbetacaroteneequivalenttotwocarrotsaday.Theresultsshowednoevidenceofanybenefitforcancer,heartdisease,ordeathrate,but,unliketheresultsoftheCARETstudy,therewasnoincreaseoflungcancerevenamongthesmokers.Theconclusionwasthatbetacarotene(atthislowdose)byitselfisuseless,butthatevidencefromotherstudiesindicatesthatvitaminEremainspromising.TheinvestigatorsalsostatethattheincreasedlungcancerriskreportedbytheCARETandATBC(seebelow)studiesisnotconsistentwiththedietaryevidence,andthatthecancer-promotingaction(ifreal)ofbetacarotenemaybeconfinedtoheavysmokers.
Betacaroteneinducesbloodvesselstogrow;becausecancersneednewbloodvesselsinordertoexpand,thiscouldexplainwhyinsomecasesbetacarotenemightpromotetumorgrowth[191].Betacarotene,itisrecommended,shouldnotbegiventopeoplewhohaveahighcarcinogenintake,suchassmokers.Anotherhypothesishasbeendevelopedtoexplainwhybetacarotenemayleadtotheincreaseinlungandprostatecancerreportedbythestudiesreviewedabove[112].TheactiveformofvitaminDhasananticancereffectincertaintissues,whichincludelung,prostate,andcolon.BetacarotenecaninterferewithvitaminDsynthesis.Furthermore,betacaroteneisstoredintheskin,andthismayblockthestimulatingeffectofultravioletradiationonvitaminDsynthesisintheskin.IntheATBCtrialinFinland,345ofthesubjectsdevelopedyellowingoftheskin.Thissupportsthehypothesisthatgivingexcesslevelsofoneantioxidantmayinduceashortageinanotherantioxidant,thusunderliningonceagaintheneedtogivesuchantioxidantsinabalancedformula.So,insmokers,itmightbewisetoaddvitaminDtobetacarotene
supplements.IthasalsobeensuggestedthatthereasonwhybetacarotenedoesnotworkinsmokersisthatthesepeoplehavealowvitaminCstatusand,aswesaw,vitaminCisinvolvedinrecyclingvitaminE[20].Thus,onthishypothesis,smokersneedvitaminsCandEratherthanbetacarotene.
AthirdnegativepaperbytheATBC(Alpha-Tocopherol,BetaCaroteneCancerPreventionStudyGroup)inFinland,inwhich29,137males
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whowereheavysmokersweregiven20mgofbeta-caroteneand50mgofvitaminEperdayforanaverageofsixyearsinadouble-blind,placebo-controlledstudy,reportedan18percentincreaseintheincidenceoflungcancer,moreprostatecancer,andan8percentincreaseindeathsfromallcausesinthevitamingroup[5].However,alaterreportofthisstudyqualifiedtheseresultstosomedegreebyadmittingthattheirfindingsconflictwiththedietaryevidence[13].Additionalfindingsreportedinthisstudyshowedthatthosesubjectswithhigherserumlevelsanddietaryintakeofbeta-caroteneandvitaminEatthestartofthestudyhadalowerriskofdevelopinglungcancer.Furthermore,thevitaminEsupplementsappearedtoprotectagainstprostatecancer(down34percent)andcolorectalcancer(down16percent).Thepeoplewhogotlungcancertendedtobethosewhoalsodrankmoreheavily.Theresearchersconcludedthatlonger,evenlifetime,supplementationwillbeneededtocombatsuchaslowlydevelopingprocessascancer.
TheeditorialthataccompaniedthesereportsintheNewEnglandJournalofMedicineargues(i)thatbeta-caroteneasasolesupplementforcancerpreventioniscontraindicated,(ii)thatthevalueofantioxidantsupplementsingeneralremainsunclear,and(iii)thattheprotectiveeffectofdiet(especiallythestrongevidenceforfruits,vegetables,andgrains)remainsimportant.Buttheeditorialconcludedthatitisanopenquestionastowhethertheantioxidantsinthesefoodsareresponsible.TheconclusiondrawnfromthisapparentdebaclebytheDirectoroftheNationalCancerInstitute,whichfundedthesestudies,was:"Wedonotknowhowtoreplaceahealthfuldietandahealthfullifestylewithsimplepills"[74].
Bothoftheseeditorialcommentsseemtometobeoverreactions.Whenalltheevidenceisconsidered,ratherthanisolatedsectionsofit,severalpointsaboutantioxidantsbecomeclear.Aswehavealreadyhadcausetonoteseveraltimes,antioxidantsshouldnotbegiven
singlybecauseofthestrongevidenceoftheirteamaction.Becauseoverloadingwithonemayupsetthisdelicatebalanceandleadtobadresults,oneshouldbeskepticalaboutsingleantioxidantsforsaleonstoreshelves.Theevidenceclearlyshowsthatantioxidantsshouldnotbeconsumedsinglybutonlyaswell-balancedmixturesofmanyantioxidants.Butitisimportanttoensurethattheantioxidantmixturecontainsenoughofthekey
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antioxidants,inparticularvitaminsEandC.Manymixturesonsalecontaininsufficientquantitiesoftheseantioxidants.However,ifadoctormeasuresantioxidantsinapatient'sbloodandfindsthatoneortwoarelow,itisallrighttotakesupplementsoftheseunderthedoctor'sdirection(moreonthislater).InfairnessitmustbepointedoutthatthesefactswerenotknownadecadeorsoagowhentheNationalCancerInstitutetrialsweredesigned.Noonetodayshoulddesignaprospectivetrialbasedonjustoneoreventwoantioxidants.
Itwouldbewisenottogivebetacarotenebyitselftoheavysmokers.Itisalsounreasonabletoexpectthatantioxidantscouldreversethebadeffectsofmanyyearsofheavysmoking(anaverageofthirty-nineyearsintheFinnishstudy).Moreover,thesubjectsintheFinnishstudyweregivenonly50mgperdayofvitaminE(inadditiontothebetacarotene),whereastheeffectivedosewouldseemtobetentimesasmuch.Inaddition,theyweregivensyntheticvitaminE,whichischemicallydifferentfromnaturalvitaminE,aswesawinpart1.Itmustalsoberememberedthatbothheartdiseaseandcancerdevelopslowlyandprogressivelyoveralongperiod.Thevalueofantioxidanttreatmentcouldbetterbetestedbygivingitearlyoninthepathologyandmaintainingtheeffectivedosageforalongerperiod.OmennhasalsodrawnattentiontotheseflawsinallofthemajorATBC,PS,andCARETstudies:choiceofhighrisk-subjects,choiceofasingleantioxidant,toolowadose,andtooshortatrial[153].InatextbookonantioxidantsPackerandDiplockstatethatthisstudyshouldbe"viewedwithcaution"[155].AstheCarotenoidResearchInteractiveGroupconcluded,"Althoughcarotenoidsshouldnotbeconsidereduniversalpreventersofdisease,itisequallyinappropriatetodownplaybetacaroteneasa'passingfad'"[28].
In1996betacarotenehadapieceofgoodnewsforachange.Omageetal.gaveagroupofnormalwomenadietverylowinbetacaroteneforsixty-eightdays[152].Theyfoundthatthemeasuresforfat
oxidationintheblood(conjugateddienes)wereraisedsignificantlyattheendofthetrial.Theyconcludedthatthisresult"supportsthesuppositionthatbetacarotenemayhaveanimportantroleinantioxidantdefense."
Fourstudiespublishedinthe1990smeasuredbloodlevelsofantioxidantswithrespecttocancerrisk.
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(1)Knektetal.inHelsinkistudied36,265Finnswithaneight-yearfollow-up[107].TheyfoundthatlowplasmalevelsofvitaminEwereassociatedwitha1.5increasedriskforcancer,particularlygastriccancer.Inotherwords,highserumlevelsofvitaminEappearedtoprotectagainstcancer.
(2)Sthelinetal.,inaSwissstudyof2,974maleswithatwelve-yearfollow-up,showedthatlowlevelsofbetacarotenecorrelatedwithhigherrisksforlungandstomachcancer[205].Inthisstudybetacaroteneappearedtoprotectagainststomachcancer.
(3)InastudycarriedoutinMaryland,Comstocketal.tookserumsamplesfrom25,802peoplefrom1974to1975[35].Thesesampleswerekeptfrozenuntil1989,bywhichtime436oftheseindividualshaddevelopedcancer.Theirserumantioxidantlevelswerecomparedwiththoseof765matchedcontrolsfromthegroupwhohadnotdevelopedcancer.TheresultswerethathighbetacaroteneandvitaminElevelswereassociatedwithastrongprotectiveeffectagainstlungcancer.Lycopene(theantioxidantfromtomatoes)showedastrongprotectiveeffectagainstpancreaticcancer.However,thisstudywasbasedononlyoneblood-levelmeasurementofnutrients,andthesebloodlevelsareliabletofluctuateaccordingtothediettakenovertheperiodbeforethemeasurement.Inanotherstudyplasmalevelsofantioxidants(vitaminsCandE,urate,andglutathione)wereshowntobelowingastriccarcinomapatients,andthemeasuresoffatoxidationwerehigher.Butwecannotdeducefromtheseresultswhetherthelowplasmalevelsofantioxidantscontributedtothecauseofthecancerorwerearesultofit.
(4)Last,Ziegleretal.measuredthelevelsofsixcarotenesinapopulationofJapaneseHawaiiansinrelationtotheriskofdevelopingcancerofthelung,esophagus,larynx,throat,andmouth[244].Theyfoundthatlowlevelsofalpha-carotene,betacarotene,beta-
cryptoxanthin,andlycopenecorrelatedwithahighincidenceoflungcancer.Thiswasparticularlytrueinthecaseofalpha-carotene(morethanbetacarotene).Othercancerscorrelatedwithlowlevelsofalpha-carotene,betacarotene,andbeta-cryptoxanthin.Theyconcludedthatothercarotenoids,notonlythebetter-knownbetacarotene,appearedtobeimportant.
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Thus,tosummarizethesefourstudies:
VitaminEwasprotectiveintwostudieswhereitwasmeasured(1,3).
Beta-carotenewasprotectiveinthreestudies(2,3,4),althoughinstudy(4)othercarotenesweremoreprotectivethanwasbeta-carotene.
Twoleadersinthisfield-HelenWisemanandBarryHalliwellofKing'sCollege,London-havepublishedareviewofthemechanismsbywhichreactiveoxygenspeciespromotecancer[234].Theynotethat"itisincreasinglyproposedthatreactiveoxygenspeciesandreactivenitrogenspeciesplayakeyroleincancerdevelopment,especiallyasevidenceisgrowingthatantioxidantsmaypreventordelaytheonsetofsometypesofcancer."Antioxidantsmayhelppreventcancerdevelopmentby(i)preventingstructuraldamagetoDNA;(ii)affectingthemechanismbywhichcellscommunicatethroughchemicalsignals;(iii)affectingtheactivityofgenesandproteinsthatrespondtostressandthatacttoregulatethegenesinvolvedincancerouscellgrowth.
SOMEINDIVIDUALCANCERS
STOMACHCANCER.
Severalwell-conductedstudieshaveshownthatvitaminCsupplementshaveastrongprotectiveeffectagainstcancerofthestomachandesophagus.ButrecentdatasuggeststhatthismayhavelesstodowiththeantioxidantpropertiesofvitaminCandmoretodowiththefactthatvitaminCcanneutralizethepotentcancerproducingnitrosaminesfoundinthestomach.Nitrosaminesarederivedfromsmoked,cured,orspicyfoods,whichshouldthereforeeitherbeavoidedortakeninsmallquantities.Infouroutoffivestudies,
vitaminCsupplementsreducedthelevelsofnitrosaminesingastricfluid,reducedtheexcretionoftheirmetabolicendproductsintheurine,loweredtheabilityofthegastricfluidtoinducemutations(aprecancerousstep),andraisedthelevelofactivityofDNArepairenzymesthatprotectagainstcancer.
Bukinetal.havestudiedpatientswithintestinalhyperplasia,aprecancerousconditionofthestomach[25].Inthisconditionthestom-
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achtissuecontainsraisedlevelsofaprotooncogeneODC(ornithinedecarboxylase),whichplaysaspecificandimportantroleinpromotingtheformationoftumors.Theinvestigatorsconductedadouble-blind,placebo-controlledstudyoftheeffectonthetissuelevelofthisprotooncogeneofgivingvitaminE(400mgperday)andbeta-carotene(20mgperday)topatientsoveraone-yearperiod.BiopsiesofthestomachliningshowedthatvitaminEreducedODCactivityby65percentbytheendoftheyear,andbeta-carotenereducedODCactivityby50percent.Inthegroupreceivingplacebo,therewasnosuchreduction.ExaminationoftheareasofintestinalmetaplasiainthestomachrevealedthatvitaminEproducedsignificantshrinkageofthemetaplasticareasintenoutoffourteenofthepatientsinoneyear.Beta-caroteneproducedsignificantshrinkageinnineoutofeighteenpatients.Therewasnoshrinkageoftheseareasinthepatientstakingplacebo.Thisstudymayillustrateanimportantpoint,namelythatantioxidantsaremorelikelytobeeffectiveduringtheprecancerousstagethanduringthestageafterthedevelopmentofanactualcancer.
BREASTCANCER.
Mostofthestudiesinthisareahaveyieldedconflictingornegativeresults.AgoodreviewhasbeenprovidedbyKimmicketal.[104].Threeofspecialinterestwarrantdescription.Onestudy,inwhichtherewere262casesofbreastcancerand273normalcontrols,suggeststhatthetypeofbreastcancermaybeanimportantfactorindeterminingtheresponsetoantioxidanttherapy[4].Thecancerpatientsweredividedintotwogroups-thosewithnegativeandthosewithpositivefamilyhistories.TheintakeofvitaminsCandEandbeta-carotenefromdietaryhistorieswasestimated,anditwasfoundthatinthegroupwithanegativefamilyhistory,beta-caroteneappearedtobeprotective,whereasvitaminsCandEwerenot.Inthegroupwithpositivefamilyhistories,however,vitaminEseemedtobeprotective,whereasbeta-caroteneandvitaminCwerenot.
Freudenheimetal.studied297patientswithbreastcancerand311normalcontrols[58].Theinvestigatorsacceptedthenotionthatadietrichinfruitsandvegetablesprotectsagainstbreastcancerandsetouttodeterminewhichantioxidantsinthesefoodswereimportant.TheirresultsshowedthatadietrichinvitaminsCandE,andthecaroteneslutein
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andzeaxanthinaswellasfiberderivedfromfruitsandvegetables,reducedtheriskofbreastcancer,whereasbeta-cryptoxanthin,lycopene,andfiberderivedfromgraindidnot.Themostimportantfactorsinreducingriskwerethetotalamountoffruitsandvegetableseatenand,amongindividualitems,carotenes,lutein,andzeaxanthin.Theauthorsstressedthatalltheseindividualcomponentsprobablyhaveateameffectandthatthereareprobablyrelevantfactorsinfruitsandvegetablesofwhichwearestillunaware.
Lockwoodetal.carriedoutatwo-yearsurveyof32patientswithbreastcancerthathadspreadtotheaxillarylymphnodes[127].TheygavetheANICAprotocol-amixtureofantioxidantsandminerals(includingbetacarotene,vitaminsCandE,selenium,gamma-linoleicacid,and90mgofvitaminQ10)-andfoundthatnopatientsdied(theexpectednumberwasfour);noneshowedfurthermetastasesorweightloss;theneedforpainkillerswasreduced;andsixpatientsshowedapparentremission.Theauthorsrecommend300mgperdayofvitaminQ10toattainabloodlevelof20µg/ml.Thewidemixtureofantioxidantsmaybeakeytotheirapparentsuccess.
However,otherinvestigationshaveyieldedconflictingornegativeresults.Wecanonlyconclude,onthebasisofpresentevidence,thatbreastcancerdoesnotrespondconsistentlytodietarymanipulation,whichconfirmstheearlierdatafromepidemiologicalstudies.Thismaybebecausebreastcancer(aswellasprostatecancer)isgreatlyinfluencedbyhormonalfactors.Also,cancerislikelytobeagroupofrelateddiseaseswithdifferentpathologies.Clearly,morestudiesusingawidemixtureofantioxidants,likethoseofLockwoodetal.[127],shouldbeundertaken.Thisconclusionissupportedbyareviewthatstatesthathumanstudiesare"limitedbutpromising"andrecommendsthatantioxidantsshouldalwaysbegivenasacomprehensivemixture[104].
LUNGCANCER.
Ziegleretal.attheNationalCancerInstituteconcurthatthereisconvincingevidenceoftheprotectiveactionoffruitsandvegetablesagainstlungcancerbutnoconvincingevidenceastowhichindividualantioxidantsmaybeimportant[243-245].However,thesameresearchgroupinapopulation-basedstudyofcarotenesinsmokersfoundthatadiethighinfruitsandvegetableswassignificantlyprotectiveagainst
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lungcancer,buttheyconcludedthatbetacarotenewasnotthedominantfactor[246].Intakesofalpha-carotene,yellowandorangevegetables,anddarkgreenvegetables(whichcontainluteinandzeaxanthin)wereeachmorepredictiveofreducedlungcancerriskthanwastheintakeofbetacarotene.TheNetherlandsCohortStudyonDietandCancer,aprospectivestudyofmorethan100,000Dutchmenandwomenovera6.3-yearperiod,showedasignificantcorrelationbetweentheamountofvegetablesinthediet(excludingpotatoes)andalowlungcancerrate[71].Themostprotectivevegetableswerecauliflower,endive,andlettuce.Alowconsumptionoffruit(especiallycitrus)wasassociatedwithincreasedlungcancerrisk.
Thecomplexityofthisfieldisillustratedbytworeportspublishedina1997issueoftheAmericanJournalofEpidemiology.Thefirst,byYongetal.,wastheprospectiveepidemiologicalNHANESIstudyof3,968menand6,199womenaged25to74yearswithamedianfollow-upofnineteenyears[238].TheymeasuredtheintakeofantioxidantvitaminsduringthistimeandfoundthatvitaminCwashighlyprotectiveagainstlungcancer.ThequarterofpeoplewiththehighestintakeofvitaminC(computedfromananalysisofthediet)hadsignificantlylowerratesoflungcancerwhencomparedwiththequarterofpeoplewiththelowestintake.However,noadditionalprotectionseemedtobegainedbytakingsupplements.VitaminEandcaroteneswereprotectiveonlyamongpeoplewhowerecurrentsmokers.TheauthorsadmitthattheirfindingcouldbeexplainedbytheusualcomplicationthatpeoplewhotookmorevitaminCintheirdietalsowerethosewithgenerallyhealthierlifestyles,andthatitwasperhapsthelatterfactorthatwasprotectiveagainstthedevelopmentoflungcancer.However,theresearchersalsofoundthatwhenvitaminsCandEandcarotenoidsweretakentogether,theprotectiveeffectwasmuchincreased.Itseemsunlikelythatpeoplewhotakeallthreevitaminswouldhaveamuchhealthierlifestyleascomparedwith
thosewhotakeonlyoneantioxidantasasupplement.Thus,itseemsmorelikelythattheprotectiveeffectisgenuineandexemplifieswhathasbeenstressedsoofteninthisbook-theimportanceoftakingabalancedmixtureofantioxidants.
ThesecondreportwasbyKnektetal.fromFinland[1o8].Theystudied9,959Finnishmenandwomenaged15to90whowereinitially
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cancerfree.Adietaryhistorywasobtainedwithafollow-upperiodoftwenty-fouryears.Duringthistime997ofthegroupdevelopedcancer,andofthese151noapparentprotectiveeffectbyvitaminsCandEorbetacarotene,butaverystrongprotectiveeffectbyflavonoids.Thisprotectiveeffectwasforlungcanceronly.Themainsourceofflavonoids(inthiscasequercetin)intheFinnishdietisapplesandonions.(Finnsdrinklittleteaorredwine.)TheresearchersnotedthatapplesareapoorsourceofvitaminCandbetacarotene.TheyalsonotedthatFinnsingeneralhadaverylowintakeofflavonoidsascomparedwithpeopleelsewhere.Oddly,thebenefitseemedtobegainedfromapplesandnotonions.Aswehavealreadyseen,Finns,atleastsouthernFinns,seemtoreactdifferentlythandootherpopulations[5,174,175].Theirveryhighintakeoffatsandalcoholmaybeimportantcomplicatingfactors.
AnotherstudyonsmokersfoundthataddingvitaminE(100-200mg),withorwithoutvitaminC(500mg),hadnoeffectontheincreasedrateofexcretionintheurineofachemicalderivedfromoxidativelydamagedDNA[166].Theinvestigatorssuggestedthatcancer-protectingeffectsoffruitsandvegetables(atleastinsmokers)mayresultfromotheranticanceragents,suchasflavonoidsandpolyphenols,inthesefoods.Itisthereforeencouragingthatcompanieswhomakeantioxidantsupplementshavestartedaddingflavonoidsandpolyphenolstotheirpills.
COLORECTALCANCER.
Kampmanetal.studiedtheeffectofvegetablesandanimalproductsoncoloncancerriskinDutchmenandwomen[99].Theyfoundthatvegetablesreducedtheriskinbothmenandwomen,whereasredmeatincreasedtheriskinwomen.Otherstudiesoncolorectalcancerhavefailedtoachieveconsistentresultswithindividualsupplements.Someotherfactororfactorsotherthanantioxidants,suchasfiberinadiet
highinfruitsandvegetables,mayaccountforthereductionofincidenceofcolorectalcancers.
UTERINECANCER.
Again,thedatarelatingtothevalueofindividualsupplementsisconflicting.Moreover,loweringserumestrogens,achievedthroughavegetariandiet,maybemorerelevantthanantioxidantactiononestrogen-relatedcancers(e.g.,breastanduterus).Theepidemiologi-
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calevidencethatadiethighinfruitsandvegetablesappearstobeprotectiveagainstthedevelopmentofcervicalcancerwasquotedearlier[17,43]
ORALCANCER.
AreviewbyGarewalandDiplockstatesthat''allavailableevidencesupportsasignificantroleforantioxidantnutrientsinpreventingoralcancer"[62].Theyrecognizethatalcoholandtobaccouseaccountforsome75percentoforalcancerintheWest.Inepidemiologicalstudiesoftheroleofcarotenoidsinlaryngealcancer,fouroutoffourwerepositive;inoropharyngealcancernineoutofninewerepositive.Insimilarstudiesoftheprecancerousconditionofleukaplakia,eightoutofeighttrialsyieldedpositiveresults.Inaclinicaltrialusingdailydosesofbeta-carotene(30mg),vitaminC(IG),andvitaminE(800mg)in79patientswithoralcancer,55percentreportedclinicalimprovement[101].Gridleyetal.oftheNationalCancerInstitutestatethatvitaminEprotectsagainstoralandpharyngealcancer[75].
CONCLUSIONONCANCER.
Thereisavastbodyoflaboratorydata,invitroandinanimals,showingacloseconnectionbetweenreactiveoxygenspecies,oxidativestress,andtheinitiationandprogressofcancer.AsstatedbyFrankeetal.,"evidencefortheinvolvementofendogenouslygeneratedfreeradicalsandoxidantsincarcinogenesisandotheragingrelateddiseasesiscompelling"[57].Althoughthereisgeneralagreementthatadietlowinsaturatedfatsandhighinfruitsandvegetablesisofcrucialimportanceinthepreventionofmanyformsofcancer,thereisstillagreatdealofdisagreementastowhattherelevantagentsinfruitsandvegetablesare.Thereisalsowidespreaddisagreementaboutthevalueofantioxidantsupplements.However,throughallthismurkageneralpicturearises.Somecancers-oral,upperrespiratorytract,lung,andhighergastrictract-seemtobemore
amenabletopreventionbydietarymeansthanothers-breast,uterus,prostate,andbloodcell.Moreover,dietarymechanismsotherthanantioxidantactionappeartobeimportantinsomecases-forexample,theantinitrosamineactionofvitaminCinthecaseofstomachcancerandtheactionofdietaryfiberincolorectalcancer.Butitremainsclearatthistimethatadietrichinavarietyoffruitsandvegetableswinshandsdownoveranyvitaminsupplements.Such
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adietprobablyprovidesmanyanticanceragentsbesidesantioxidantsaboutwhichweasyetknowlittle.Tobenefitfromtheprotectiveeffectsofdietarychemicalsitisbesttodowhatyourparentstoldyou-eatyourvegetables.
DISEASESOFTHENERVOUSSYSTEM
Thebrainisparticularlyvulnerabletooxidativestressforseveralreasons:
1.Itusesoxygenatafasterratethananyothertissue.
2.Itscellularmembraneshavehighlevelsofeasilyoxidizablefat.
3.IthasnaturallylowlevelsofthetwoantioxidantenzymesCATandGSHpx.
4.Nervecellsthatarekilledcannotbereplaced,unlikeothercellsinthebody.
5.Severalofthebrain'schemicals,calledneurotransmitters,thatareusedassignalsbetweennervecellsinducebiochemicalreactionsthatleadtothereleaseofreactiveoxygenspecies.
VitaminC(alsoknownasascorbicacidorascorbate)hasmanyfunctionsinthebrainunrelatedtoitsvitamineffectinpreventingscurvy(whichhastodowithbuildingupconnectivetissueintherestofthebody).ThebrainhasveryhighlevelsofvitaminCandaspecificmechanismforpumpingitoutofthebloodintobraincells.BrainvitaminCplaysaroleinthesynthesisandreleaseofmanyneurotransmitters,anditalsohasanimportantroleasthemainwater-solubleantioxidantinthebrain.
Thefollowingbraindiseasesareassociatedwithoxidativestress.
STROKE.
Astrokeresultsfromtheblockageofanarterytothebrain.Atfirstthebrainsuffersfromlackofoxygen.Thisiscalledtheischemicstage.Then,whenthebloodreenterstheaffectedregionofthebrain(calledthereperfusionstage),moredamageiscausedbylargequantitiesofreactiveoxygenspeciesthatarereleased.Theseareprimarilyresponsibleforthebraindamagesufferedbythestrokevictim.Itisthereforepossiblethatantioxidants,iftheycanbegivensoonenough,maypreventsomeofthisdamage.
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DOWN'SSYNDROME.
Down'ssyndromeisassociatedwiththeoverproductionofoneformofreactiveoxygenspecies-hydrogenperoxide-owingtoageneticfaultintheantioxidantenzymesuperoxidedismutase(SOD)(seepart1)thatmakeshydrogenperoxide.ThesepatientshaveanextracopyofthegeneforSODonchromosome21.Thismayseemparadoxical-whyshouldanantioxidantenzymemaketoomuchofanoxidantlikehydrogenperoxide?TheansweristhattheSODactsonthestronglyoxidantsuperoxideionandturnsitintoweaklyoxidanthydrogenperoxide.Thelatteristhendetoxifiedbythesecondenzymecatalase(CAT),whichthusactsintandemwithSOD.InDown'ssyndrome,thebrainleveloftheenzymethatdetoxifieshydrogenperoxide-CAT-isincreasedinresponsetotheSOD-inducedoverproductionofhydrogenperoxide.ButevenwiththeelevatedCATactivity,theoverallexcessofhydrogenperoxideisharmfultobraintissue.
ALZHEIMER'SDISEASE.
ThebraininAlzheimer'sdiseasehastwoneuroanatomicalabnormalitiesvisibleunderthemicroscope.Onetypeconsistsofroundblobscalledplaques,theotherofmassesofproteinfilamentscalledneurofibrillarytangles.
TherearetwomaintypesofAlzheimer'sdisease,onewithageneticbackgroundandtheotherwithout.SomecasesofAlzheimer'sdiseasearecausedbyadefectivegeneonchromosome14thatcodesfortheproductionofaproteincalledpresinilin-I.Thisproteinformsanintegralpartofnervecellmembranes.Cellscontainingthisabnormalgenearemuchmorevulnerablethannormalcellstooxidativestress.
ThebraininAlzheimer'spatientsshowsevidenceofoxidativestress,withdamagetobrainproteinsbeingpronounced[73].Anabnormaltoxicbrainprotein-beta-amyloid-concentratesinplaquesandistoxic
tonervecellsbyareactiveoxygenspecies-basedmechanism.Thismechanismincludesactivationoftheenzyme(calledprostaglandinHsynthase)thatstartsthesynthesisofinflammation-producingprostaglandins.Levelsofthisprostaglandin-producingenzymearegreatlyraisedinsidethedamagednervecellsinthedisease.Inresponsetothis,thelevelsoftheantioxidantenzymeglutathioneperoxidase(GSHpx)inthebrainisraisedtocombattheincreasedoxidativestress.Butanotherantioxidantdefense-beta-carotene-getsoverwhelmed,soitslevelsfall.Inthe
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cerebralcortexofthebraininAlzheimer'sdiseasethereisalsoevidenceofincreasedfatoxidation.Thus,thebraininAlzheimer'sissubjecttoanintenseinflammatoryprocessmediatedinpartbyexcessproductionofreactiveoxygenspecies.
Thereisnowconsiderableevidencetosuggestthatnonsteroidalanti-inflammatoryagents,suchasaspirinoribuprofen,maypreventordelaytheinitialonsetofsymptomsofAlzheimer'sdisease.Outofsixteenstudiesonthistopic,fifteenhadpositiveresults.McGeeretal.conductedananalysisofseventeenepidemiologicalstudiesandfoundasignificantcorrelationbetweentheuseofanti-inflammatorydrugsandprotectionagainstAlzheimer'sdisease[133,1341].Thediscoveryofthiscorrelationwasmadebyaccident.Aseriesofpatientswithrheumatoidarthritiswerebeingtreatedinalong-termstudywithanti-inflammatoryagents.ThephysiciansweresurprisedtodiscoverthatfewerofthesepatientsdevelopedAlzheimer'sdiseasethanwasexpected.Manypeopletakeanaspirinaday,asthishasbeenshowntoreducetheriskofheartattack.Itnowseemslikelythattakinganti-inflammatoryagentsmayalsoreducetheriskofgettingAlzheimer'sdisease.Anti-inflammatoriesinhibittheenzymethatmakestheinflammation-producingprostaglandins;thisreactionisalsoapotentproducerofbrain-damagingreactiveoxygenspecies.Thus,itisreasonabletosuggestthatantioxidantsmayhelphere,too,althoughfurtherstudiesareneeded.InthecaseofapatientwhowasunfortunateenoughtohavebothAlzheimer'sdiseaseandaformofcancerknownasmultiplemyeloma,thepowerfulimmunosuppressantsandanti-inflammatoryagentsgiventohimforthetreatmentofhiscancerproducedasignificantimprovementinhisAlzheimer'sdiseasefortwoyears,untilhisdeathfromthecancer[102].
TheNewEnglandJournalofMedicinereportedtheresultsofadouble-blind,placebo-controlled,randomizedtrialofvitaminE(2G
perday),orthedrugselegiline(whichcutsdowntheproductionofreactiveoxygenspeciesinthebrain),oracombinationofthetwo,in341casesofmoderateAlzheimer'sdiseaseinamammoth,twenty-three-centerstudyovertwoyears[183].Practicalindicatorsweremeasuredsuchastheneedforhospitalization,lossofabilitytoperformtheactionsneededfordailyliving,developmentofseveredementia,anddeath.TheresultsshowedasignificanttherapeuticeffectforbothvitaminEandforselegilinein
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preventingthefurtherdevelopmentoftheillness.However,thecombinationofthetwodidnotconferanyaddedbenefit.Inthesameissue,DrachmanandLebercommentedonthispaper,pointingoutsomecaveats.TheyagreedthatitisnowjustifiedtotreatthisstageofAlzheimer'sdiseasewitheithervitaminEorselegiline(butnotboth).ButthestudydidnotaddressthequestionastowhethervitaminEwouldpreventordelaythesubsequentdevelopmentofAlzheimer'sdiseasewhengiventoyounger,apparentlynormalpeople.Anydouble-blind,placebo-controlledstudydesignedtoanswerthisquestionwouldbeenormouslydifficultandexpensivetocarryout.ThisstudysuggeststhatvitaminEmaybeofbenefitincasesofestablishedAlzheimer'sdisease,presumablybecauseofitsantioxidantproperties.Thereisnowabundantevidenceofpowerfuloxidativestressinthedisease.Sincethereiseveryscientificindicationthatantioxidantsaremoreeffectivewhengivenbeforetheoxidativestresshasproducedactualcellulardamage(seealsothesectionondiabetes),thenmedicalcommonsensesuggestsgivingpeopleatriskforAlzheimer'sdiseasevitaminEsupplements(ataround400-800mgperday).Thislevelwilldothemnoharmifsomeelementaryprecautions,relatingtovitaminKandhemorraghicstroke(seepart3),arefollowed.
PARKINSON'SDISEASE.
Parkinson'sdiseaseiscausedbythedestructionofcertainnervecellsinapartofthebraincalledthesubstantianigra(or"blacksubstance,"socalledbecausethesenervecellscontainlargeamountsoftheblackpigmentneuromelanin).Thesecellsuseachemicalcalleddopamineastheirneurotransmitter.Withinthecellsofthesubstantianigra,dopamineiseasilyoxidizedtoformaredsubstancecalleddopaminochrome,which,inturn,formsneuromelanin.Thisprocessreleasesalargeamountofreactiveoxygenspecies.Inaddition,dopaminochromeishighlytoxictonervecells.Atbirththecellsof
thesubstantianigracontainnoneuromelanin;rather,itgraduallyandsteadilyaccumulatesduringlife.Normallyneuromelaninisusefulinthatitgetsridofthetoxicdopaminochrome.Italsobindsandneutralizestoxicheavymetalatomssuchasironandmanganese.However,inexcess,ititselfbecomestoxicanddestroysthenervecell.Whenacriticalmassofthecellsinthesubstantianigrahavebeendestroyed,Parkinson'sdisease
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results.Inthisdisease,thereissevereoxidativestressinthesubstantianigrawithexhaustionofglutathione.(Recallfrompart1thatglutathioneisthemainantioxidantinsidethecellsofthebrain,whilevitaminCisthemainantioxidantinthewateryfluidbetweenthecells.)Hydrogenperoxidealsointerfereswiththestorageofdopamineinsidethecellsinthesubstantianigra[48].Dopamineinsideitsstoragevesiclesisprotectedbyantioxidantsfromoxidation;butdopamineoutsidethesevesiclesismoreliabletooxidation,becauseinthislocusithaslessantioxidantprotection.Glutathionescavengeshydrogenperoxide,so,whenitslevelfalls,hydrogenperoxidelevelsriseanddopaminecannotbestoredproperly.Itthusbecomesmorevulnerabletoconvertbyoxidationtodopaminequinones,poisonouscompoundsthatdamagethecells.Becausethecellsofthesubstantianigracontainthemajorpartofthedopamineinthebrainandsupplyittotherestofthebrain,theirdestructionleadstothesymptomsofdopaminedepletion.Thesearetremor,rigidity,andmentalimpairment-thesymptomsofParkinson'sdisease.
ThecurrentprincipaltreatmentofParkinson'sdiseaseistoadministerL-DOPA,theprecursorofdopamine.Inthebrain,L-DOPAistakenupandturnedintodopaminetoreplacethedopaminemissingintheParkinsonianbrain.However,thebeneficialeffectsofL-DOPAtreatmentlastonlyashorttime:thebasicdestructiveprocesscontinues,withthedopaminecellsinthesubstantianigrabeingkilledoffatasteadyrate.AfteraboutfiveyearsthediseaseprogressestoaconditionasprofoundasifL-DOPAhadneverbeenadministered.Clearlywemustdeveloptherapydesignedtopreventthekillingofthesecellsandnotmerelysupplybyartificialmeanstheproduct(dopamine)thattheymake.Aswithdiabetes,forwhichthemaincurrenttherapyisinsulin,thetreatmentstrategysupplieswhatismissingbutdoesnotaddressthemainproblem,whichistopreventthedestructionoftheinsulin-producingbeta-cellsofthepancreasthat
causedthediseaseinthefirstplace.
IfParkinson'sdiseaseisdueinparttooxidativestress,itwouldbelogicaltotryantioxidanttherapyinanattempttodelayorpreventParkinson'sdisease.Moreover,L-DOPAitselfisalsometabolizedinthebraintothetoxiccompounddopachrome,whichcanfurtherdamagethebraincells.Forthisreason,Menaetal.advocatevitaminCsupplementsduringL-DOPAtherapy[140].Parkinson'ssufferersalsohaveahigherinci-
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denceofheartdiseasethandonormals,possiblybecauseofthesameraisedlevelofoxidativestress.
PeoplewithParkinson'sdiseasetypicallyhavenormalbloodlevelsofvitaminsA,C,andE,andScheideretal.haveclaimedthatthereisnocorrelationbetweenthediseaseandthepreviousintakeofantioxidantvitamins[188].AcontraryresultwasobtainedbydeRijketal.[41]inastudyof5,342subjectsaged55to95.Asemiquantitativefood-intakequestionnairewasgivenfrom1990to1993.Thirty-onesubjectssubsequentlydevelopedParkinson'sdisease;theyhadasignificantlylowerintakeofvitaminE,butnotvitaminCorflavonoids,thandidthosewhodidnotdevelopParkinson'sdisease.AnothersuchstudyinHawaiiproducedthesameresult.
TherehavealsobeensomestudiesoftreatmentofcasesofestablishedParkinson'sdiseasebyantioxidants,buttheresultshavebeeninconclusive.However,thedamagetothepigmentedneuronsofthesubstantianigrastartsatleastfiveyearsbeforetheearliestclinicalsymptomsofParkinson'sdiseaseshowthemselves.Therefore,givingantioxidantstopatientsalreadywithsymptomsmaybeacaseofshuttingthestabledoorafterthehorsehasgone.AsthereisatpresentnowaytoidentifywhichpeoplewilldevelopParkinson'sdiseasefiveyearslater,theonlywaytoapplythisstrategywouldbetoraisetheantioxidantintakeforeveryoneovertheageof40.
MOTORNEURONDISEASE.
Motorneurondiseasegoesbyseveralnames.ManyknowitasLouGehrig'sdisease;themedicaltermisamytrophiclateralsclerosis,orALS.ThephysicistStephenHawkingsuffersfromALSandhasbeenalong-termsurvivorofthedisease.Mostpatientsdiewithinthreetofiveyearsofdiagnosis.Itiscausedbyaselectivedeathofthelargemotornervecellsinthespinalcord.Withoutthetransmissionofmotorsignalstothemuscles,widespreadparalysisresults.Thereare
twoformsofthedisease,geneticandsporadicornongenetic.Intheformertype,thegeneatfaultistheoneformakingtheantioxidantenzymeSODandisfoundonchromosome2.Thebraininthesecasesshowslowerantioxidantdefensesandchemicalsignsofincreasedfatoxidation.
ReiderandPaulsontelltheinterestingstoryofhowvitaminEwasusedsomefiftyyearsagototrytotreatALS[173].Thepatientsincluded
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thefamousbaseballplayerLouGehrig,alaswithoutbenefit.However,theseresearcherssuggestthat,nowthatsomecasesofthediseasehavebeentracedtoageneticallyabnormalantioxidantenzyme(SOD),thesemayrepresentasubtypeofthediseaseandthatfurthertrialsareindicated.
HUNTINGTON'SDISEASE.
Huntington'sdisease,alsoknownasHuntington'schorea,ischaracterizedbyprofounddementia,abnormalemotionalreactions,disturbedbehavior,andinvoluntarymovementscalledchorea.Itiscausedbyamutationinadominantgeneandischaracterizedbyseverenerve-celllossinthebasalgangliaandpartsofthecerebralcortex.Thebasalgangliaarestructuresinthebrainthatcontroltheprogrammingofvoluntarymovements.Withintheaffectedbraintissues,theenzymesinthemitochondriathatprovidetheenergythecellneedsareseverelyaffected.DNAremovedfromanaffectedpartofthebrainofapatientwithHuntington'sdiseaseshowsanabnormalchemicalchangethatwasbroughtaboutbyattackbyareactiveoxygenspecies[23].
SCHIZOPHRENIA.
Thisisasevereillnessthataffectsoneineveryhundredpeople.Itischaracterizedbyhallucinations,delusions,paranoia,andemotionaldisturbances.Itusedtobethoughtofasapsychologicalillness,butwenowknowthatitisanorganicdiseaseofthebrain[202].Therearetwotypesoftheillness.TypeIshowsacute"positive"symptomssuchashallucinationsandexcitement.Ithasastronggeneticcomponent,respondswelltotreatmentwithantipsychoticdrugs,andthebrainshowsnosignsofphysicaldegenerationonascan.TypeIIischaracterizedby"negative"symptomssuchassocialwithdrawalandapathyandrespondspoorlytomostmedicinesexceptclozapine,anatypicalantipsychoticdrug.IntypeIIcasesthereisnogenetic
componentbutthebraintypicallyshowssignsofphysicaldamageonascan.
ModerntechniqueshaveshownatthemicroscopiclevelthatthebrainintypeIIschizophreniahasbeendamaged.Inmanybrainregionstherearefewernervecellsthannormal;inafewareasthereappeartobetoomany;and,inotherkeyareas,thereisalossoftheinterconnectionsbetweencells.Becausethejobofthebrainisconductedmainlybyneuronssendingeachothersignals,lossofpartofthenetworkthatcarriesthesesignalscanhaveseriousconsequences.
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Inthissystem,ifthenumberofconnectionsbetweenneuronsisreducedbelowacertainlevel,neuralcomputationscannotproceednormally,andphenomenacalledparasiticfocidevelopinwhichacertaincomputationentersintoaviciousrepetitivecyclethatcannotbechangedbyexternalinfluences;inthehumanbrainaffectedbyschizophrenia,delusionsandhallucinationsresult.
Howarethesekeyconnectionslostinschizophrenia?Inordertounderstandthemechanism,wemustdiscusssomespecificsofwhathappensattheseconnectionsbetweenneurons.Thegapbetweentheendofoneneuralprocess(oraxon)andthenextneuroniscalledasynapse.Thechemicalthatcarriesthemessagefromoneneurontothenextacrossthisgapiscalledaneurotransmitter.Neurotransmitterscaneitherbeexcitatoryorinhibitory.Excitatoryneurotransmitters,whenreleasedacrossthesynapse,causethesecondneurontofire.Inhibitoryneurotransmitters,whenreleased,causeittostopfiring.InthebrainintypeIIschizophreniathereisa50percentlossofexcitatorysynapses.
Themainexcitatoryneurotransmitterinthehumanbrainisachemicalcalledglutamate,morefamiliarasthemonosodiumglutamateusedinmuchAsiancooking.Glutamateisaverytoxicmolecule,anditisremarkablethatthebrainusesitforsuchakeyroleinneurotransmission.Yetthistoxicityhasafunction.Glutamateexertsitstoxicactiononnervecellsbymeansofthereactiveoxygenspeciesitgeneratesinthesecond(postsynaptic)neuron.Thisprocessisoneofthewaysinwhichtheglutamatesynapsecangetridofunwantedsynapses.Synapses,evenintheadultbrain,areinaconstantstateofflux.Newsynapsesarecontinuallybeingformedandoldonesdeleted.Weareconcernedherewiththemechanismthatleadstosynapsedeletion[201].
Atsynapticconnectionswhereglutamateistheneurotransmitter,there
arethreetypesofreceptors.OneoftheseiscalledtheNMDAreceptor.Activationofthisreceptorresultsinaninflowofcalciumionsintothenervecell,whichstartsacascadeleadingtoactivationoftwoenzymes.OneoftheseisprostaglandinHsynthase(orPGHsynthase),whichwehaveseenbeforeastheenzymethatinitiatesprostaglandinsynthesis.TheactivationofPGHsynthaseleadstothereleaseoflargequantitiesoftoxicreactiveoxygenspecies,includinghydrogenperoxide.Hydrogenperoxideitselfisnotveryreactivebutitcandiffusewidelyinandoutofcells.
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Undercertainconditions,especiallyinthepresenceoffreeiron,itcanformmoretoxicreactiveoxygenspeciessuchasthehydroxylradical.
TheotherrelevanteffectoftheNMDAreceptoristoactivateanotherenzymecallednitricoxidesynthase,whichmakesnitricoxide(NO).Nitricoxideisagascapableofdiffusingwidelyfromitspointoforigin.Thereisevidencetoshowthatboththesecompounds-hydrogenperoxideandnitricoxide-haveimportantfunctionsinthebodyassignalingmolecules.Moreover,theybothhavepro-oxidantproperties,and,beingfreelydiffusiblemolecules,theycanentertheglutamatesynapseitself.Heretheycanactuallyeliminatethesynapse.Oneimportantfactorthatdetermineswhetherasynapseismaintainedordeletedisthebalanceinthesynapsebetweenneurotoxicoxidants(hydrogenperoxideandnitricoxide),whichwilltendtodeletethesynapse,andneuroprotectiveantioxidants,whichwilltendtomaintainit.
Theantioxidantdefensesatthesynapseconsistofthreemaincomponents.ThefirstisvitaminC,whichisreleasedbytheaxonterminalduringtheprocessinwhichtheactionofglutamateisterminatedbypumpingitbackintothesynapticterminal,whereitcanberecycledtobeusedagain.Thus,thebrainveryneatlyarrangesforafloodofprotectivevitaminCtobepumpedintothesynapsejustwhenthedamaginghydrogenperoxideisdiffusingbackfromthepostsynapticsite.Thesecondisanantioxidant-carnosine-whichisfoundinglutamatenerveterminalsandreleasedtogetherwiththeglutamate.Thethirdisthemostinteresting.Attachedtothesideofmostglutamatesynapsesisadopamineterminal,whichistriggeredwhenanyactivityoftheorganismisrewardedbywhatwecallpositivereinforcement-thatis,foodorsomeotherpleasurablestimulus.Someofthedopamineitreleases,wheneversuchastimulusisreceived,enterstheadjacentglutamatesynapse.Dopaminehappenstobeapowerfulantioxidant-akeyfactdiscoveredbytwoscientistsin
Japan,JiankangLiuandAkitaneMori[125].Dopamineherewillincreasetheantioxidantstatusofthesynapseandtiltthebalanceofsynapsegrowthanddeletioninthedirectionoftheformer.Thismaybeoneofthebiochemicalwaysinwhichconditionedreflexesarebuiltupandlearningtakesplace:ittendstostrengthenthosebehaviorsthatleadtopositivereinforcement,becausethecircuitsthatunderliethatbehaviorarestrengthenedbygrowingmoresynapses.Likewise,iflessdopamineis
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released,thebalanceinthesynapsetiltstheotherway,andtheprobabilityincreasesthatthatsynapsewillbepruned.
However,usingdopamineasanantioxidantinthiswaycarriesarisk.For,intheabsenceofsufficientlevelsofotherantioxidantsinthesynapse,dopamineeasilyconvertsspontaneously(byoxidation)totoxicquinones,includingdopaminochrome.Furthermore,undertheseconditionsofloweredantioxidantdefenses,nitricoxidewillalsoconverttopoisonouscompoundscalledreactivenitrogenspecies(suchasperoxynitrite),whichwillattackdopamineandhastenitsconversiontothetoxicquinones.Thesereactivenitrogenspeciesanddopaminequinoneswillattackthesynapseandcandestroyit.
EvidencesuggeststhatitmaybethissystemthatgoeswrongintypeIIschizophrenia:
1.Antioxidantsmopuporotherwiseinactivatethereactiveoxygenspeciesthatwouldotherwisedeletethesynapse.Antioxidantsalsoslowdowntheproductionofquinonesfromdopamine.Theseantioxidantmechanisms,particularlythoserelatingtovitaminCandtoGSHpx,arefaultyinschizophrenia.
2.Theblackpigmentinthebrain,neuromelanin,whichismadefromthetoxicquinones,isameansoftakingthemoutofcirculation.Thereispreliminaryevidencethatneuromelaninisabnormalinsometypesofschizophrenia.
3.Somebraindopamineisnormallyturnedintoacompoundcalled5-cysteinyldopamine,whichisinitselfagoodantioxidant.Thisprocessalsopreventstheformationofthetoxicquinones.Levelsofthiscompoundareelevatedintheschizophrenicbrain.However,thiscompoundcanitselfleadtotheproductioninthebrainofneurotoxicderivatives(calledbenzothiazines)thathavebeenimplicatedinthecauseofParkinson'sdisease.
4.Anotherdefenseagainsttheformationoftoxicquinonesfromdopamineaprocesscalledtransmethylation,convertsthemintoharmlesscompounds.Inthisprocessamethylgroup(composedofoneatomofcarbonandthreeofhydrogen)isattachedtoanactivesiteonthemoleculeandrendersitnontoxic.MyworkwithLelandTolbert,JohnKelso,andothershasshownthatthisreactionisalsoweakinschizophrenia.
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Directchemicalevidencenowexiststhatthequinonesderivedfromdopaminearepresentinthehumanbrain.Indeed,theymustbe,becausetheylieonthechemicalsyntheticpathwaybywhichneuromelaninismade,andneuromelaniniscertainlypresentinthebrain.
Epinephrineanddopaminearecloselychemicallyrelated-infact,epinephrineismadeoutofdopamine.In1954Hoffer,Osmond,andIdiscoveredthatthequinonederivativeofepinephrine,adrenochrome,whengiventonormalpeopleproducesinthemmanyofthesymptomsofschizophrenia[89].Thisexperimentwasconfirmedbythreeothergroupsofscientists,oneintheUnitedStates,oneinGermany,andoneinCzechoslovakia.Epinephrineisusedinthebrainasaneurotransmitterbyonlyonesmallsetofnervecells.Itismorelikelythatcloserelativesofadrenochrome-thequinonesderivedfromdopamineandnorepinephrine-areinvolvedintheschizophrenicprocess.Norepinephrineisfoundinanucleusofthebraincalledthelocuscoeruleus;thenervecellsherealsocontainneuromelanin,indicatingthatnorepinephrine,too,ismetabolizedinthebrainbythequinonepathway.Thereisevidencethatthenervecellsofthenorepinephrinepathwayarealsodamagedinschizophrenia,andthisdamagemaybesimilarlyaffectedbyreactiveoxygenspeciesandthequinonederivativeofnorepinephrine.Noonehasasyettestedtheeffectofthesequinonesderivedfromdopamineandnorepinephrinegiventonormalpeople,butitmaywellbethattheyactashallucinogens,liketheircloserelativeadrenochrome,thequinonederivedfromepinephrine.
Thus,tosummarize,reactiveoxygenspeciesandoxidizedderivativesofbraindopaminecalledquinonesmaybeinvolvedinschizophrenia,ontheevidencethattheyareagentsthatmayprunesynapsesandinschizophreniadefensesagainstthem(antioxidants,O-methylation,andneuromelaninformation)arefaulty.Itisthereforeworth
investigatingwhetherboostingantioxidantdefensesand/orcuttingdownreactiveoxygenspeciesproductionisofbenefitintheillness.
Peoplewithschizophreniaarelowinantioxidantdefenses.PlasmalevelsofvitaminCarelow,andmorevitaminCthannormalisneededtoraisebloodlevelstoagivenlevel,suggestinganincreasedusageincombatingoxidativestress[211].Glutathionelevelsinbloodarealsolow,andthereisastrongcorrelationbetweenlowlevelsoftheantioxidantenzymeGSHpxandtheraisedlevelsofbraindamageinschizophrenia.
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MyworkwithHofferandOsmondhasdemonstratedthatschizophreniamayalsobeassociatedwithadiminishedcapacityfordealingwithtoxicmetabolitesinthebrainproducedfromtheoxidationofepinephrine,dopamineandnorepinephrine.Manyantischizophrenicdrugs,suchaschlorpromazine,arepowerfulmoppers-upofthetoxichydroxylradicalandinhibitorsoffatoxidation.Thepotentantischizophrenicdrughaloperidolactsdifferently:itmopsupanotherkindofreactiveoxygenspeciescalledhypochlorousacid.Thus,itispossiblethatthebeneficialeffectsofthesedrugsinschizophreniamaybedueinparttotheirantioxidantproperties.ReportshaveindicatedthatantioxidantssuchasvitaminCbenefitschizophrenicpatients[1oo].Moreworkinthisareaseemstobecalledfor.
PSYCHOLOGICALSTRESS
Someexperimentswithratshaverecentlyshownthatseverepsychologicalstressinrats(inducedbyrestrainingtheanimalforeighthours,whicharatfindsexceedinglystressful)leadstosevereoxidativestress.Theoxidativestressischaracterizedbyexhaustionofantioxidantdefensesandanelevatedlevelofoxidizedfats.Theprincipaldamagingagentinthistypeofstressisthehydroxylradicalthatproducesstomachulcersinratsunderthesecircumstances[39].Suchulcersmaybepreventedbyantioxidants.Thereareasyetnohumanexperimentsdesignedtoinvestigatethepossiblerelationbetweenpsychologicalstressandoxidativestress,buttheresultsofsuchatrialwouldbeinteresting.
DIABETES
Thisdiseaseiscausedbyadefectinsugarmetabolismowingtoalackofinsulin.Evenwithinsulintreatment,itstillremainsamajorcauseofblindness,kidneyfailure,disordersoftheheart,brain,andvascular
systems,andlimbamputations.TypeIdiabetes,alsocalledinsulin-dependentdiabetes,ischaracterizedbymarkedlackofinsulin,itsearlyageofonset,itsseverity,andtheneedtotakeinsulininjections.Insulinisproducedbythebeta-cellsofthepancreas.TypeIdiabetesisanautoimmunediseaseinwhichthebody'simmunesystem
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mistakesitsownbeta-cellsinthepancreasforforeignintrudersandproceedstodestroythembyamechanismthatincludesanattackbyreactiveoxygenspecies.Beta-cellsnormallyhavealowlevelofantioxidantprotection.Levelsofreactiveoxygenspeciesarealsogenerallyincreasedthatis,notonlyinthepancreas-becausethediabetic'swhitecellsproducemorereactiveoxygenspeciesandmoreprostaglandinsaresynthesized.(Youwillrememberfrompart1thattheprocessofmakingprostaglandinsreleaseslargeamountsofreactiveoxygenspecies.)Moreover,twomechanismsthatinvolvetheabnormalmetabolismofbloodsugar-glucose-alsoyieldreactiveoxygenspeciesasaby-product.Thereisalsoevidencethatfreeironandcopperionsarereleasedfromthestoreswheretheyareusuallykeptfromdoingharm.Freeironandcoppercirculatinginthebodyfluidsareextremelytoxicoxidants.Thus,indiabetestheincreasedlevelsoffreeironandcopperionsaddstothelevelofoxidativestress.
Animalstudiesshowthatantioxidantscanpreventoralleviatevariousformsofexperimentallyinduceddiabetes.Indiabeticratsthesyntheticantioxidantprobucolprotectstheheartagainstoxidativestress.Inhumandiabetes,bloodlevelsofmarkersforoxidativestressareincreasedandlevelsofprotectiveantioxidantsdecreased(inparticularuricacidandvitaminC)[133].VitaminsCandEinhibitfatoxidationindiabetics.Noninsulin-dependentdiabeticshavesignificantlyloweredlevelsofvitaminCintheblood[133].TestsofvitaminCinhumandiabeticshaveshownthatitimprovesvascularperformance,leadingtoafallinbloodlevelsofLDL(bad)cholesterolandariseinprotectiveglutathionelevels[160].DiabeticsalsohavebeenreportedtohaveloweredbloodlevelsofvitaminA,glutathioneperoxidase,anduricacid,aswellashavingsignsofoxidativedamagetotheDNAinbloodcells[78].Inothertestsnicotinamide(vitaminB3)atadosageof3Gperdayreducedtheneedtogiveinsulintodiabetics.VitaminB3isoneofthehelpersoftheantioxidantactionof
vitaminEasdescribedinpart1.Santinietal.concludefromtheirstudiesthatininsulin-dependentdiabetesoxidativestressisincreasedandantioxidantdefensesaredefective''regardlessofduration,metaboliccontrolorpresenceofcomplications"[184].
Chaseetal.reportedaninitialnegativeresultinapreliminarytestofnicotinamideindiabeticchildrenandadolescents[33].Thoughthis
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wasdisappointing,theyreasonedthatbythetimeactualdiabetesdevelops,thedamagetothepancreaticbeta-cellshasalreadybeendone.Therefore,theysuggestedthatantioxidanttherapybestartedintheprediabeticstage.Theytestedthistheoryinafurtherstudyoftwenty-twochildrenathighriskfordevelopingdiabetes.Thesechildrenhadafirst-degreerelativewithdiabetes,aswellasantibodiesintheirbloodagainstbeta-cellsandimpairedinsulinrelease.Theygaveeightchildrenplaceboandfourteenchildren3Gperdayofnicotinamide.Alleightofthechildrenonplacebodevelopeddiabetesbytheendofthestudy,butonlyoneofthechildrenonnicotinamidedid.Theauthorsfeltthatthisresultwasmostpromisingandagainstressedthatthenicotinamidemustbegivenbeforethebeta-cellsaredestroyed.
Thesyntheticantioxidantsilymarinhasbeentestedindiabeticpatientswhohadcirrhosisoftheliver[223].Thirtypatientsweregiveninsulinonlyandtheotherthirtyweregiveninsulinplussilymarin.Aftertwelvemonthsthepatientswhohadhadthesilymarinshowedsignificantclinicalimprovementascomparedtothecontrols.Indicesusedincludedfastingbloodglucoselevels,glycosuria,fastinginsulinlevels,insulinrequirements,andMDAlevels.
Inastudyofeightydiabeticswithdamagetotheretinaandperipheralnerves,twentypatientsweregiventheantioxidantlipoicacid,twentyreceivedvitaminE,twentyweregivenselenium,andtwentyreceivedplacebo[156].Thefirsttwogroupsshowedasignificantimprovement,asmeasuredbylessfatoxidation,betterlegsensation,improvedreflexes,andlessalbuminintheurine.TheantioxidantlipoicacidiscurrentlybeingusedinthetreatmentofdiabeticnervedamagebyDr.Packer'sgroup.Lipoicacidcrossestheblood-brainbarrier,whichN-acetylcysteinedoesnot.Adouble-blind,placebo-controlledstudyhasbeencarriedoutontheeffectsoflipoicacidonadisorderofheartfunction(cardiacautonomicneuropathy)thatoccurs
asacomplicationofdiabetes[241].Thirty-ninepatientsreceived800mgperdayoflipoicacidandthirtyfourothersreceivedplacebo.Theinvestigatorsreportedamodestbutsignificantimprovementinheartfunctioninthegroupthatreceivedthelipoicacidwhencomparedwiththosethatreceivedtheplacebo.Therewerenosideeffectsnoted.Anotherdouble-blind,placebo-controlledtrialoftheantioxidantaminoacidL-arginineinhumandiabetesfoundthat
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itstronglyreducedthelevelsoffatoxidation.Thecomplexinteractionsbetweenfatintakeandantioxidantstatusindiabeticshasbeenillustratedbyastudyinwhichasimplechangeindiet(lessfat,morecarbohydrate)ledtoanincreaseinbloodlevelsofvitaminsCandE[6].Thisisbecausethelowerfatintakeproducedlessoxidativestress,thussparingtheantioxidantvitamins.
PregnantdiabeticratsfedeitherthesyntheticantioxidantBHT(butylatedhydroxytoluene)orvitaminEhadalowerincidenceofoffspringwithcongenitalabnormalitiesthandiduntreateddiabeticrats.ThiswasconfirmedbyasecondstudyinratsusingacocktailofvitaminE(400mgperday)andtwocompoundsreportedtobedeficientindiabetesarachidonicacidandmyo-inositol[172].Theuntreateddiabeticratshadahighincidenceofabnormaloffspring,includinga23.7percentrateofneuraltubedefects,ascomparedwith4percentofnormalrats.Thetreatmentreducedtheincidenceofneuraltubedefectsinthediabeticratstonormallevels.Theseabnormalitiesarethoughttobeduetohighblood-sugarlevelsindiabetesthatmayinterferewiththetransportofthekeyantioxidantglutathioneinthebody.Inhumans,thebirthdefectsassociatedwithdiabetescanbepreventedbyastrictadherencetoatreatmentanddietaryregimendesignedtolimitraisedblood-sugarlevels[171].Antioxidantsupplements,however,maymakethistreatmentmoreeffective.Nohumanworkhasasyetbeendonetotestthishypothesis.Theconclusionisthatantioxidanttherapyseemspromisingindiabetes,especiallyiftheprediabeticstagecanbediagnosedandtreated.
EYEDISEASES
CATARACTS.
Thetransparentcrystallineproteinsoftheeye,unlikemostproteins,
arenotcontinuallyreplaced.Theyarealsoatriskforoxidativedamagefromultravioletlight.InanimalexperimentsvitaminsCandEandsomesyntheticantioxidantsprotectedthelensagainstoxidativestress.TheimportanceofvitaminCisindicatedbythefactthatthereisanactivetransportsystem(pump)foritinthewateryhumorandthelens.Severalepidemiologicalstudieshavesuggestedaprotectiveroleforantioxidantsagainstcataractformation.
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(1)Hankinsonetal.carriedoutastudyofmorethan50,000nursesforaneight-yearfollow-upperiod[77].Theymeasuredtheintakeofantioxidantsinthedietandcomparedthelowestintakegroupwiththehighestintakegroupforcarotenesandfounda39percentreductionincataractsinthelatter.VitaminsCandEandriboflavininthedietwereineffective.Spinachratherthancarrotswasthemosteffectivevegetable.DietaryvitaminChadnoeffectnordidmultivitamintablets.However,vitaminCsupplements(averagedoseof50-500mgperday)takenfortenormoreyearsledtoa45percentreductionincataracts.Theauthorsquotethreepreviousstudiesthatobtainedthesameresultandonethatfailedtodoso.WhydidthestudybyHankinsonetal.findthatdietaryvitaminCwasnotprotectivewhereasvitaminCsupplementswere?Probablybecauseofthehigherdoseinthecaseofsupplements.
(2)Inacarefullycontrolledtrialinvolving152subjectsand152controls,vitaminCsupplements(300-600mgperday)overfiveyearsappearedtoreducethecataractrateby70percent[178].VitaminEsupplements(400mgperday)forfiveyearsappearedtoreducetherateby55percent.
(3)Astudyof1,380ophthalmicoutpatientsagedfortytoseventy-nineindicatedthattheregularuseofvitaminsupplementssignificantlyloweredtheincidenceofcataract[21].
(4)Afifteen-yearfollow-upstudycomparedforty-sevenpatientswithcataractsandninety-fourmatchedcontrols[106].Lowserumlevelsofbeta-caroteneandvitaminEcorrelatedwithmorecataractformation.Therewasathreefolddifferenceintheincidenceofcataractsbetweentheone-thirdofsubjectswhohadthehighestserumlevelsandtheone-thirdwhohadthelowest,indicatingthattheseantioxidantsprotectedagainstcataractformation.LevelsofvitaminCwerenotmeasured.
(5)Jacquesetal.,inastudyof247femalesaged56to71,showedthatvitaminCsupplementsreducedtheincidenceofearlylensopacitiesby77percentandofmoderatelensopacitiesby83percent.However,thevitaminChadtobegivenforaminimumperiodoftenyearsforthebenefittobeobtained.Shorterperiodsshowednoeffect.Theresearchersconcludethat"long-termconsumptionofvitaminC
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supplementsmaysubstantiallyreducethedevelopmentofagerelatedlensopacities"[97].
Thesestudiescanbesummarizedasfollows:
VitaminEappearedtobeprotectiveintwostudies(2and4).
VitaminCappearedtobeprotectiveinsixstudiesandnotinone(1,2,5,andthosequotedby1).
Carotenesappearedtobeprotectiveintwostudies(1and4).
Vitaminsupplementsappearedtobeprotectiveinonestudy(3).
However,whenonetakesintoaccountthattherearethreetypesofcataract-nuclearsclerosis,corticalopacities,andpostsubcapsularthingsgetmorecomplicated.Therehavenotbeenenoughstudiesasyettodeterminereliablywhichsubtypesrespondordonotrespondtoantioxidanttherapy.
Thereactionoftheexpertstoallthisinformationhasbeenmixed.Christenconcludesthattheepidemiologicaldataare"wildlyconflicting"withmanyuncontrolledconfoundingvariables[34].Gershoffsaystheyare"promisingbutunproven"[63].Taylorbelievestheconsensusisimpressiveandsuggeststhattheoptimumlevelsofnutrientsforthedelayofcataractshouldbedefinedassoonaspossible[214].OptimumlevelsforvitaminEwill,hesuggests,probablyrequiresupplements.
Diplockclaimsthat"thelaboratoryandepidemiologicalevidenceisnowsostrongthatitisessentialtoensurethatthepopulationisadequatelysuppliedwithE,Candbeta-carotene"[43].
MACULARDEGENERATION.
Inthecaseofadvancedage-relatedmaculardegeneration(adiseaseinwhichthecenteroftheretinadegenerates),onelargemulticenter
studyof356patientsand520normalcontrolshasshownthatahigherdietaryintakeofcarotenoidswascorrelatedwitha43percentreductionofmaculardegeneration,butvitaminsCandEwereineffective[192].Theparticularcarotenoidsmostlikelytobeinvolvedwerenotbeta-carotenebutluteinandzeaxanthin,whicharefoundindarkgreenleafyvegetablessuchasspinach,collardgreens,kale,andturniptops;carrotsareverylowinthesetwocompounds.However,thisresultmayhavelittletodowithantioxidants.Luteinandzeaxanthinhappentobe
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thetwodominantyellowpigmentsinthemacula(center)oftheretinathatfilteroutthedamagingbluelight.Beta-caroteneandlycopene(fromtomatoes)areabsentfromthemacula.Increasingtheserumlevelsoflutein,bydietarymanipulation,leadstoincreasedluteininthehumaneye.Thusluteinandzeaxanthinemayacttoprotecttheretinadirectlybytheirfunctionasnaturalpigmentsagainstlightdamage,ratherthanasgeneralantioxidants.However,anotherstudyof167casesofmaculardegenerationimplicatedlowlevelsoflycopeneratherthanluteinandzeaxanthininthedisease[131].RedbloodcellsincasesofmaculardegenerationhavebeenreportedtohavesignificantdecreasesinlevelsofSODandglutathioneperoxidase[148].Landrumetal.suggestthatlong-termsupplementationforindividualshavinglowlevelsofmacularpigmentcouldbeofbenefit[115].Adietrichindarkgreenleafyvegetablesand/orsupplementswithluteinandzeaxanthin,andwithtomatoesand/orsupplementsoflycopene,mayhelpprotectagainstthisformofblindness.
RESPIRATORYDISEASES
Thelungisatriskofoxidativestressbecauseofthelargeamountsofoxygenthatpassthroughitwhenwebreathe.Oxidativestressinthelungleadstodamagetothecellmembranes,inflammation,andbronchoconstriction.
ASTHMA.
Asthmaisachronicrespiratorydisorderthatresultsinconstrictionofthebronchianddifficultyinbreathing.Itisassociatedwithoxidativestressbecausethewhitecellsintheepithelialliningofthebronchiproducemorereactiveoxygenspeciesthannormal.RiskfactorsforasthmaincludelowdietaryintakeofvitaminsCandEandselenium,highbodyiron,andexposuretoenvironmentaltoxinssuchaslead,
whichpoisonsseveralenzymesinthebodyonthepathwaymakingtheimportantantioxidantglutathione.Ithasbeenshownineightoutoftenstudiesthatthechildrenofsmokershaveanincreasedincidenceofasthma.Oxidantexposureininfancymayleadtoasthmainlaterlife.AsthmaticshavelowbloodlevelsoftheantioxidantenzymeGSHpxandlowlevelsofthetracemineralselenium,whichisapartofthisenzymecomplex.Thisleadstoincreasedoxidativestressfromreactiveoxygenspecieslike
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hydrogenperoxide,whicharenormallyneutralizedbyselenium.NewZealandhaslowlevelsofseleniuminthesoil,andNewZealandershaveahighincidenceofasthmaandahighmortalityfromthedisease.
AlargeepidemiologicalsurveyconfirmedthatalowdietaryintakeofvitaminCiscorrelatedwithasthmaandthatthesymptomsofasthmaaremadeworsebyenvironmentaloxidantsandbetterbyvitaminC[79].VitaminCisthemajorantioxidantinthefluidthatcoversthesurfaceofthelungwhereitprotectsagainstenvironmentaloxidants,includingtoxicnitrogenoxidesinsmog.Antioxidantdefensesareparticularlylowduringanacuteasthmaticattack.Thecurrentevidencesuggeststhatantioxidantsshouldprotectagainstasthmaandalleviateitssymptoms.Interestingly,beta-blockers(suchasisoproterenol),whicharewidelyusedinasthma,arealsopotentantioxidants;theauthorsofonestudysuggestthatthismaycontributetotheirtherapeuticeffectinasthmabymoppinguptheexcessreactiveoxygenspeciesfoundinthedisease[68].
AstudycarriedoutinruralChinafoundthatincreasingtheintakeofvitaminCby1oomgperdayimprovedlungfunctionasmeasuredbyforcedexpiratorytests[92].Theimprovementwasestimatedtoequaloneyearofaging-relatedlossoflungfunction.Astudyof393nonsmokersfoundthatbloodlevelsofvitaminCwereinverselyrelatedlevelsofachemicalmarkerforfatoxidation[190].ThissuggestedthatvitaminCwasprotectiveagainstfatoxidation.Arecentdouble-blind,placebo-controlledstudyofseventeenasthmaticadultsshowedthatsupplementationwithvitaminE(400mgperday)andvitaminC(500mgperday)ledtoareductionintheirsensitivitytoozonethatwasmostmarkedinthesixmostseverecases[223].
ACUTERESPIRATORYDISTRESSSYNDROME(ARDS).
InARDStheantioxidantdefensesinthebloodarelowered,andthereisafallintheprotectiveelementsoftheplasma.Inonestudythirty-
twopatientswithARDSweretreated,halfwithconventionaltreatmentandhalfwithantioxidants(vitaminsCandE,selenium,andN-acetylcysteine)[186].Themortalityrateinthefirstgroupoverfourweekswas71percent,inthesecondgroup37percent-averysignificantdifference.InasecondclinicalstudythesyntheticantioxidantEUK-8wasfoundsignificantlytoprotectagainstthetypeofacutelunginjurythatoccursduringshock.Inadouble-blind,
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placebo-controlledprospectiveclinicaltrialinvolvingfiveintensivecareunitsintheUnitedStatesandCanada,ARDSpatientsweregiventheantioxidantsN-acetylcysteineandprocysteine[13].Therewasnoeffectonoverallmortality(possiblybecausethesamplesizewassmall),buttherewasasignificantimprovementinlungandheartfunction.
RESULTOFCIGARETTESMOKING.
Anotherlungconditioninwhichreactiveoxygenspeciesplayaroleistheresultofexposuretocigarettesmoke-bothactivesmokingandpassiveexposuretosmoking.Cigarettesmokingisthesinglelargestcauseofprematuredeathinindustrializedsocietiesandofcourseaffectsmanyothersystemsbesidesthelungs.Tobaccosmokehashighlevelsofreactiveoxygenspeciesandpro-oxidantoxidesofnitrogen,aswellasavarietyofcancer-producingchemicals.Everypuffofcigarettesmokeinhaledcontains1015(1followedby15zeros)moleculesofreactiveoxygenspecies.Insmokersindicesofoxidativestressareraised,whereasthelevelsofvitaminCandtheantioxidantenzymeCATarereducedinthefluidliningtheirlungs.GlutathionelevelsarereducedinthelungcellsthemselvesandplasmalevelsofvitaminC(butnotvitaminE)arealsoreduced.Smokersalsoexcreteinthebreathexcessiveamountsofthegasethane,whichisaproductoffatoxidation.Themorecigarettestheysmokethemoreethanetheyexcrete.VitaminEreducesfatoxidationinbothsmokersandnonsmokers.Inonethreeweekstudytensmokersweregivenanantioxidantcocktailthatincluded6mgofbeta-carotene,200mgofvitaminE,and250mgofvitaminC[8].Thereresulteda29percentreductionintheamountofethaneexcreted.Smokersexcretefourtotentimesthenormalamountof8-OH¬G(ameasureofoxidativeattackonDNA)thannormals.
Brownetal.studiedfiftysmokersandfiftynormalcontrolsina
double-blind,crossovertrialofvitaminE(280mg)versusplacebo[22].Theymeasuredthesensitivityoftheredbloodcellstooxidativestressinducedbythepro-oxidanthydrogenperoxide,aswellaslevelsofkeyantioxidantenzymes.TheyfoundthatvitaminEprotectedtheredbloodcellsagainstoxidativestressinbothsmokersandnonsmokersandraisedthelevelsofsomeantioxidantenzymes.Lykkesfeldtetal.,usingnewandaccuratemethods,measuredtheamountofvitaminCandoxidizedvitaminCinthebloodofsmokers[130].TheyfoundthatlevelsofordinaryvitaminCwere
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belownormal,whereasthelevelsoftheoxidizedformofvitaminCweremuchabove(18times)normal.WhenvitaminCrecyclesvitaminE,thevitaminCisturnedintooxidizedvitaminC(seepart1).ThiswasevidenceofsevereoxidativestressanddepletionofvitaminC.TheyrecommendedthatallsmokersneededtomaintaintheirbloodlevelsofvitaminCatabout70µL/L.Thiswouldrequireanintakeofatleast200mgperdayofvitaminC.Lehretal.saythatthereisnowenoughexperimentalandepidemiologicalevidencetowarrantclinicaltrialsofvitaminCindiseasesassociatedwithcigarettesmoking,suchaspulmonaryemphysema,chronicobstructivepulmonarydisease,andatherosclerosis[120].Itwouldseemlogicalthereforethatsmokerswhocannotstopsmokingshouldincreasetheirantioxidantdefenses.
EXPOSURETOSMOG.
Nitrogendioxide(NO2)isaprominentandpowerfuloxidantpresentinsmog.InhumanplasmaexposedtoNO2,thereisarapidfallinlevelsofvitaminsCandQ10andaslowerfallinvitaminE,bilirubin,andprotectiveproteingroups.HumansexposedtoexcessivelevelsofNO2(suchasglasscraftsmenandbraziers)showgreatlyexcessivelevelsoffatoxidation(uptoonehundredtimesthenormal)andareinspecialneedofantioxidantprotection.Thesamemaybetrueofpeoplewholiveinsmog-ladencitiessuchasLosAngelesandMexicoCity,butspecificstudiesneedtobecarriedouttodeterminethisrelationship.
Dieseloilfumescontainasmuchasonehundredtimesasmuchtoxicnitrogenoxidesasdogasolinefumes.Ifbloodplasmaisexposedtodieseloilfumes,thereisaprofoundfallinvitaminCanduratelevelsandalesserfallinvitaminElevels.Thebloodproteinsalsoshowsignsofoxidativedamage.
AGING
Agingisnotadiseasebutanormallifeprocessthatinvolvesphysicalandbiochemicalchangesinthebody.Itisgenerallyagreedthattheonlyreliablewaytoincreaselifespanthroughdietistoeatless(knowninthefieldascaloricrestriction).Thisinsightisrelatedtoacorrelationbetweenincreasedfoodconsumptionandoxidativestress.Astudyofratsfedasmuchastheywantedandratsgivenarestricteddietshowedthattheincreasedcaloriesinthedietledtoraised
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measuresoffatoxidationintheblood.CaloricrestrictionlowersreactiveoxygenspeciesproductionandlevelsofproteinandDNAoxidation.ItalsoreducesthenormalfallwithageoftheantioxidantenzymeCATinblood.Themechanismforthiseffectisunknown,butitmayinvolvetheenzymesandsmallmoleculesresponsiblefortheremovalofreactiveoxygenspecies.
Thereissomeevidencetosuggestthatincreasedoxidativestressandadeclineinantioxidantdefensesplayaroleinaging.Therearereportsofhighlevelsofreactiveoxygenspeciesanddecreasedantioxidantactivityinelderlypeople,particularlyintheadrenalglandsandinthebrain[81].Theagingbraincontainshigherthannormallevelsofoxidizedfats.Moreover,theagedhaveimpairedimmuneresponsesthatrendersthemmoresusceptibletoinfectionslikeinfluenzaandpneumonia.Increasedintakeofsomeantioxidantnutrients-especiallyvitaminE-improvestheimmuneresponse[141].
Leewenburghetal.claimthatagingisassociatedwithafallinbothenzymaticandsmall-moleculeantioxidantdefensesinmanyimportantorgans(liver,brain,heart,kidney,butnotmuscle)[118].Antioxidantdefensesintheadrenalglanddecreasewithage,which,inturn,leadstoadeclineintheproductionofadrenalcorticalhormones[7].Theadrenalsofyounganimalsarewellprotectedagainstoxidativedamage,andhavehighlevelsofseveralantioxidants,includingvitaminsCandE,andshowlowlevelsoffatoxidation.AdietdeficientinvitaminEleadstoincreasedfatoxidationintheadrenalsanddecreasedproductionofadrenalhormones.ArecentstudyinHollandfoundthatbeta-caroteneappearedtoprotectagainstage-relatedlossofcognitivefunction.However,Calsetal.haveconcluded,followingastudyinParis,thatagingbyitselfdoesnotleadtooxidativestressaslongasgoodgeneralhealthandgoodnutritionaremaintained[27].
Thereisasyetnoevidencetoshowwhetherantioxidantsupplementswillactuallyslowtheagingprocessinhumans.Furtherstudiesareneeded.Butthisremainsapossiblebenefittobehopedforbypeoplewhoattendconscientiouslytotheirantioxidantintake.However,whetherincreasedoxidativestress,weakenedimmunefunction,anddecreasedantioxidantdefensesarethehallmarksofnormalagingorareduetotheimpairednutritioncommonamongmanyelderlypeopleisstillanopenquestion.
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HIVINFECTIONANDAIDS
AIDSpatientsareunderpowerfuloxidativestressfromtwosources.Oneistheexcessiveproductionofreactiveoxygenspeciesbytheirwhitebloodcells.Theotheristheexcessiveproductionofcertainproteins,calledcytokines,thatcontroltheimmunesystem.Manycytokinesalsostimulateprocessesthatresultinoxidativestress.Thesepatientsshowdeficienciesofzincandselenium(twodietarymetalsthatareessentialfortheproperfunctionofantioxidantenzymes)andoftheantioxidantglutathione.Asthediseaseprogresses,reactiveoxygenspeciesproductionandlevelsoffatoxidationincreaseasaresultoftheattackoftheHIVvirusontheimmunesystem.Thisresultsinaprogressiveloweringofantioxidantdefenses,inparticularbloodlevelsofglutathione,zinc,selenium,vitaminE,carotenoids,andGSHpx,whichareexhaustedbythehighlevelofcontinuingoxidativestress.AIDSpatientsshowexcessfatoxidation.Levelsoffatoxidationstarttoriseearlyinthediseasebeforeanysymptomsdevelop.
SomeexpertsrecommendthattreatmentofAIDSshouldincludetherapiesaimedatrestoringdepletedglutathionelevels.OnesuchagentisNAC,whichhasbeensafelyusedinmedicinefortwenty-fiveyears.TheonlyproblemisthatNACisincompatiblewithtrypsin,chymotrypsin,andmanyantibiotics.ThereshouldbeagapofatleasttwohoursbetweentakingNACandanyofthese.IthasalsobeensuggestedthatNACmayexertpartofitsreportedtherapeuticactionbyraisingbloodcystinelevels,whicharelowinthedisease.Theselowlevelsleadtocomplicationssuchasmusclewastingandreducedimmuneresponses[46,47].Otherpromisingdrugsofthesametypearealphalipoicacidandglutamine,whichthebodyusestomakeglutathione.
AcontraryopinionisexpressedbyAilletetal.oftheInstitutPasteur
[2].Followingtest-tube(invitro)studiesofsomeantioxidants,includingNAC,onthereplication(growthandspread)oftheHIVvirus,theinvestigatorsfoundthattheantioxidantswereonlypartlysuccessfulinblockingHIVmultiplicationinonetypeofwhitebloodcellandunsuccessfulinothertypes.Moreover,theyfoundthatthehighdosesofantioxidantsneededtoproducethismoderateeffectcausedanunwantedblockadeofotherimportantbloodcellscalledmonocytes.Theyconcludedthatthese
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antioxidantscannotcountertheintenseactivityofthemultiplicationoftheHIVvirusbutmayaggravateimmunedisturbancesinHIVpatientsbythemonocyteblockade.Moreover,inHIVpatientslowdosesofantioxidantsmayhaveaparadoxicaleffectofincreasingHIVmultiplication.ThisisunwelcomenewsforthemanyAIDSpatientswhocurrentlytakelargeamountsofantioxidantssuchasNAC.
Theeffectsofbeta-caroteneandseleniumsupplementationhavebeentestedinpatientsinfectedwithHIV.Althoughmeasuresofoxidativestresswerereduced,itwasdisappointingthattherewasnopositiveclinicaleffectnoted.Everalletal.havefoundthatvitaminCslowsthegrowthoftheHIVvirusintest-tubeexperiments[54].Moreover,thelevelofvitaminCisloweredinthebrainofpatientswhodiedofAIDS.TheinvestigatorssuggestthatvitaminChastworolesinAIDS:thefirstistoraisetheleveloftheantioxidantdefenses,andthesecondmaybetokilltheHIVvirus.
AIDSpatientswithlowlevelsofvitaminsA,beta-carotene,B6,andB12haveapoorprognosis,andsupplementsofthesevitaminsincreasethesurvivalrate[212].AnotherstudyhasshownthatHIV-infectedpatientshavealowerriskofdevelopingactualAIDSiftheymaintainahighintakeofvitaminE[I].However,ahighintakeofzincincreasesthedeathrate.Inthecaseofbeta-carotenetheoptimumamountisabout10mgperday.Toomuchisharmful.TheseresultsmaybeduetotheeffectoftheBvitaminsontheimmunesystem.
RecentlyDrögeetal.suggestedthatAIDSpatientsmustbetreatedonanindividualbasis,adjustingthedosetotheneedsofthepatientasisdoneinthecaseofinsulintreatmentofdiabetes[46].Bloodlevelsofcystine,cysteine,andglutamineneedtobemonitored.Thiscreatesdifficultiesforattemptstocarryoutdouble-blind,placebo-controlledtherapeutictrialsusingonlyonedoseofNAC.Clearly,muchmoreresearchneedstobedoneinthisfield.
SHOCK
Shockisanacutemedicalemergencycausedbyinjury,bloodloss,severeburns,infection,andsoon.Septicshock,duetoabacterialinfection,istheleadingcauseofdeathinintensivecareunits.Thebacteriumreleasesatoxinthatprovokesanoverproduction
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ofcytokinesandreactiveoxygenspecies.Septicshockpatientshaveincreasedfatoxidationratesandexhaustedantioxidantdefenses.Inanimalexperimentsantioxidants(vitaminE,NAC,andSOD-ifthisisgivenbeforethesepsisstarts)haveproventooffereffectivetreatment,buttherearestillconflictsintheliterature.Inhumanstherehavebeentwotherapeuticstudies,onewithNAC,andonewithacombinationofvitaminsEandC,NAC,andselenium.Bothstudieshadpositiveresults.
Otherformsofshock-duetobloodlossandburns-arealsocharacterizedbysevereoxidativestress.Inanimalexperiments,antioxidantswereeffectivetreatmentsofshockduetobloodlossandburns.InthesestudiesnewsyntheticantioxidantssuchasZ-103andEbselenhavebeenused.Preliminarytestsinhumansareunderway.
ISCHEMIA/REPERFUSION
Inanycondition-suchasstroke,heartattack,orduringorgantransplants-inwhichthebloodflowtoanorganisinterruptedforawhileandisthenrestarted,severeoxidativestressresults.Duringaperiodoflossofnormalbloodflow,calledischemia,evenforaperiodofafewminutes,thetissuesbecomedamagedbythelackofoxygen.Butthemaindamageoccursduringreperfusion,therestorationofthebloodflow.Alargereleaseofreactiveoxygenspeciescausedbybiochemicalchangesinthereperfusedtissueresultsinsevereoxidativestressandaloweringofintracellularglutathionelevels.Inastudyofexperimentalischemiaoftheheartinrats,antioxidants(SOD,CAT,vitaminE,anddesferoxamine)offeredeffectiveprotection,butthebestwasthesyntheticagentH290/51,whichis1ootimesaspotentasvitaminEininhibitingfatoxidation.Inkidneytransplantsischemia/reperfusioninjurycanbereversedbyantioxidants.However,LehrandMessmerhavecomplainedthat,inspiteofthestrongscientificevidencethatoxidativestressplaysakeyroleintransplant
surgery,''littleattentionispaidtotheantioxidantstatusofpatientsundergoingorgantransplants"[119].Thisisanexampleoftheslowpaceatwhichthemedicalprofessioningeneralisactuallyputtingthesenewinsightstouse.
Inthrombolytictreatmentforacuteheartattacksinhumans(inwhichthebloodclotinthecoronaryarteryisdissolvedviaacatheter
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insertedintotheheart),patientsdevelopariseinfatoxidationandafallinvitaminEandretinoids-signsofreperfusionoxidativestress.Thus,theremaybearolefortheuseofsomeofthefaster-actingantioxidantsinthrombolytictreatment.VitaminEactstooslowlytoperformthistask.AstudyofcoronaryarterybypasssurgeryshowedthatpreoperativeadministrationofvitaminEforfourweeksresultedinfewerabnormalitiesintheelectrocardiogramandfewerinfarctions(heartattacks)aroundthetimeoftheoperation[189].
Patientswithblockedlegarteriesdeveloppainduringexercise,calledintermittentclaudication,becauseofthelackofbloodflowtosupporttheexercise;theysufferfromrepeatedischemia/reperfusiondamageeverytimetheygoforawalk.Inthesecases,afteraperiodofexercise,thereisasignificantdropinantioxidantcapacityintheblood.Suchpatientsmayneedantioxidantsupplementation.
Thereisalsoevidencethatreactiveoxygenspeciesareafeatureincerebralvasospasm(contractionofthearteriesofthebrain).Inanimalsantioxidantswereeffectiveinreducingvasospasm,particularlyifappliedlocally.Thismighthavesomeapplicationinneurosurgery.
However,awarningnotehasyetagainbeenstruck.PallerandEaton,intheirstudyofreperfusionoxidativedamagetothekidney,found,quiteunexpectedly,thatglutathioneandonetypeoftheantioxidantenzymeSODwereprotectiveifgivensinglybuthighlytoxicifgivenincombination[157],whereasglutathioneandanothertypeofSODgiventogetherweresynergistic.Theyadvisethat"greatcaremustbeusedindesigningandinterpretingstudiesemployingcombinationsofantioxidants."Thisappliesparticularlywhentheseagentsareadministeredintravenously.
CYSTICFIBROSIS
Incysticfibrosis,themostcommonlethalinheriteddiseaseintheUnitedStates,ageneticmutationleadstoabnormallystickysecretionsbythemucousglands.Thesecretionsgumupthelungs,resultinginchronicinflammation.Excessiveactivityofthewhitebloodcellsresultsinanincreaseinreactiveoxygenspecies,which
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inturnpromoteexcessiveproductionoffibroustissueinthelung.MalfunctionofthepancreasresultsinaninabilitytoabsorbvitaminEproperlyfromtheintestines,whichnotonlyimpairsthegeneralantioxidantdefensesofthebodybutalsoleadstoliverdamage.Moreover,thelungsofthesepatientsgetinvadedbyabacterium(pseudomonasaeruginosa)thatisaproducerofreactiveoxygenspecies.
CysticfibrosispatientshaveverylowbetacaroteneandvitaminElevelsandhighlevelsofoxidizedfats.Givingsupplementsofbetacarotenehelpsnormalizethelevelsoffatoxidation.Thelowerthelevelsoftheprotectivebetacarotene,thehigherthelevelsofoxidationofthefats.Therefore,supplementscontainingbetacarotenecouldbeoftherapeuticvalueincysticfibrosis.Thereisalsoaneedtodevelopnewsyntheticantioxidantsthatcanbeabsorbedinspiteofpancreaticfailure.Ramseyetal.saythat"everypatientwithcysticfibrosiswilleventuallyrequiresupplementationwithfatsolublevitamins"[69].ThepotentantioxidantNACcanbegivenadequatelybymeansofanaerosolspray.Winklhofer-Roobetal.haveshownthatpatientswiththisdiseasewhohavelowbloodlevelsofvitaminCalsohavehighbloodindicesofinflammation(MDAandTGF¬levels),whereasthosewithhighlevelsofvitaminChave"clearlylowervalues"oftheseindicesofinflammation[232].TheseresearchersseethesemeasurementsasevidencethatvitaminCisprotectiveincysticfibrosis,buttheywarnthat,owingtothepossiblepresenceoffreeiron,furtherstudiesareneededtodeterminewhethervitaminCsupplementsaresafe.Freeironmightbeanimportantconstituentofthefluidliningtherespiratorytractincysticfibrosis,inwhichcasevitaminC,whichbecomesapotentoxidantinthepresenceoffreeiron,mightbetoxic.
VanderVlietetal.offeranotherwarninghere[222].Itistheoreticallypossiblethatantioxidantsbenefitthebacteriummorethanthepatient.
Thebacteriumalreadyproducesoneantioxidantitself(slimyalginate),whichmightinterferewiththeoxidantattackusedbythewhitebloodcellstokillthebacterium,ashappensinacuteeyeinfections.TheseinvestigatorsalsowarnaboutthepossibledangerpresentedbytheinteractionofvitaminCandfreeiron.Researchersdevelopinganantioxidanttherapyforcysticfibrosismustbearthesecaveatsinmind.
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THECOMMONCOLD
Twenty-fiveyearsagoNobelLaureateLinusPaulingcausedafurorbyclaimingthatvitaminCcouldalleviatethesymptomsofthecommoncold.Althoughthemedicalestablishmentgreetedthisclaimwithderision,manypeopletodaycontinuetoreachforthevitaminCbottleassoonassignsofacoldstarttodevelop.However,wenowknowthatmanyofthesymptomsofacoldareduenottothecoldvirusitselfbuttoanoverlyenthusiasticresponseofthebody'sownimmunesystemtothevirus.Duringacoldthemucousmembraneliningofthenosebecomesfilledwithwhitebloodcells,whichsecretelargeamountsoftheirmostpowerfulweapon,reactiveoxygenspecies,aimedatkillingthevirus.Unfortunately,thereactiveoxygenspeciesproducedbythemacrophagesoftheimmunesystemalsoattackthecellsofthemucousmembranethemselves,leadingtoarunnynoseanddiscomfort.Thus,thestrategyofgivingantioxidantsduringacoldisnottokillthevirus,buttoweakenthisattackbyreactiveoxygenspeciesonthebody'sowntissues.However,vitaminCdoesalsohavesomeactioninboostingimmuneresponses[40,103].
HemilandHermanhaverecentlyreexaminedthefindingsofalltwenty-oneplacebo-controlledtrialscarriedoutonthistopicsince1970inwhichIGormoreofvitaminCadaywasgiven[81].Theyfoundthatineverystudytherewasnochangeinthenumberofcolds;buttherewasasignificantfallinthedurationandseverityofthesymptoms.TheycriticizeasinadequatesomepreviousreviewsthatconcludedthatvitaminCdidnothingforacold.Althoughthereisasyetnodirectevidencetosupportthishypothesis,itisscientificallypossiblethatvitaminCcouldreducethesymptomsofacoldwhilehavingnodirectactiononthecoldvirusitself.
ACUTEINFECTIONS
Antioxidantsarenot,ofcourse,cure-alls.Eyeinfectionscausedbybacteriaaremadeworsebyantioxidants,whichinterferewiththebactericidalactionofthereactiveoxygenspeciesproducedbythemacrophages.Thismaywellapplytootheracuteinfections.
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Onecertainexceptionispneumococcalmeningitis.Inastudyofrats,theantioxidantNACprotectedagainstthisinfection[109]byreducingthebrainedemaandincreasedintracranialpressureproducedbyreactiveoxygenspecieswhosebrainlevelsareincreasedbytheinfectionandwhichareamajorcauseofdeath.TheNACdidnotinterferewiththewhitecells'useofreactiveoxygenspeciestokilltheinvadingbacteria.Inthecaseofnonbacterialeyeinflammation,animalexperimentsshowthatantioxidantsareprotective.However,itwouldbewisetotakeantioxidantsduringthecourseofanacutebacterialinfectiononlyontheadviceofadoctor.
BETA-THALASSEMIA
Thisdiseasecausessevereanemia;consequently,patientsmustundergorepeatedbloodtransfusions,whichleadtosevereironoverloadanddamagetomanyorgans.Theexcessironinducessevereoxidativestress.Livreaetal.studiedforty-twopatientsandfoundthatbloodindicesofoxidation(conjugateddienes,MDA/TABadducts,andproteincarbonyls)wereraisedtwofold[126].Bloodlevelsofmanyantioxidantswerereduced(vitaminCby44percent,vitaminEby42percent,vitaminAby44percent,beta-caroteneby29percent,andlycopeneby67percent),presumablybecausetheywereusedupbytheiron-inducedoxidativestress.Thetotalantioxidantpotentialwasreducedby14percent.Theresearcherssuggestedthatthisoxidativestressmightbethecauseofthemyocardialdamagethatisthemajorcauseofdeathinthedisease.Theyconcludedthatadministrationofantioxidantcompounds,butnotvitaminC,couldbebeneficial.ApreviousattemptwasmadetotreatthisdiseasewithvitaminE.Rachmilewitzetal.treatedeightpatientswhohadlowvitaminElevelswith750-,1,000mgperdayofvitaminEforsixteenmonths[161].Theyfoundthatthereweresomechangesinantioxidantmeasures,butthetreatmenthadnoclinicaleffect.They
concludedthatvitaminEbyitselfmightnotbeenough.
CIRRHOSISOFTHELIVER
Cirrhosisoftheliver,whichfollowsfromexcessiveintakeofalcohol,maybedueinparttofatoxidationandliverdamagefromreactiveoxygenspecies.OnetrialofvitaminEsupplements
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inestablishedcirrhosiswasineffective,butthismayhavebeenanothercaseofshuttingthestabledoorafterthehorsehadgone.
EFFECTSOFSTRENUOUSEXERCISE
Moderateexercise,plusalow-fat,highcarbohydrate,andhigh-fiberdiet,leadstoadramaticdecreaseinLDL(badcholesterol)oxidation.However,ithasbeenshownthatextremelystrenuousexerciseleadstooxidativestressandcompensatoryrisesinantioxidantenzymesandglutathione.Thisisbecauseextremeexerciseleadstomuscleischemia/reperfusionandagreatlyincreaseduseofoxygen.AthleteshavehigherlevelsofvitaminEintheirredbloodcellsandvitaminCintheirwhitebloodcellsthandononathletes.Senhaswrittenagoodreviewofthistopic[193].Heconcludedthatphysicalexerciseisprotectiveagainstoxidativestressinanumberofways.However,overdoingitcanbeharmful.AccordingtoSen,people'sphysiologicalantioxidantstatusvarieswidelyandthusaperiodicassessmentofone'ssusceptibilitytooxidativestresswouldbedesirable.Afterareviewofthemethodsthathavebeenusedtocombatoxidativestressduringexerciseandtheirresults,heconcludedthatglutathioneisineffectiveprobablybecauseitdoesnotgettowhereitisneeded.NACisconvertedintoglutathioneinthebodyandmaybeeffective,butinformationislackingontheeffectsofvitaminsCandE.Onlytwotestshavebeencarriedouttoseewhethertakingantioxidantsactuallyincreasesathleticperformance.Thefirst,onswimmers,hadanegativeresult.However,atrialofvitaminEinhigh-altitudemountaineeringshowedimprovedperformanceatlowoxygenlevels.Atpresentweknowonlythatathleteshavebetterantioxidantdefensesthandononathletes.Onewondersifathleteswhotakeantioxidantsupplementswouldcomeunderthebanonartificialaidstoimproveathleticperformance!
HYPERTHYROIDISM
Hyperthyroidismisassociatedwithincreasedoxidativestress,leadingtoincreasedfatoxidationandlowerserumvitaminElevels.Thyrotoxicmuscleandheartlesionsmaybedueinpartduetooxidativestress.Therehavenotasyetbeenanyreportsoftheuseofantioxidantsinthedisease.
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INFLAMMATORYBOWELDISEASE
Lih-Brodyetal.havestudiedbiopsiesfromtheintestinesofpatientswithtwosuchdiseases-Chron'sdiseaseandulcerativecolitis[124].MeasuringindicesofproteinandDNAoxidationaswellaslevelsofreactiveoxygenspeciesandtheantioxidantenzymeSOD,theyfoundevidenceofsevereoxidativestress.InChron'sdiseasetheyfoundraisedlevelsofreactiveoxygenspecies,iron,andSOD,aswellasthepresenceofproteincarbonyls(evidenceofoxidativedamagetoproteins)andoxidativelydamagedDNA.Inulcerativecolitistherewereraisedlevelsofreactiveoxygenspecies,proteincarbonyls,andironnotonlyintheinflamedsitesbutinnormalareasbetweentheinflamedsites,showingthattheraisedlevelswerenotjustaresultofinflammation.Inulcerativecolitisthereisfreeironoverloadfromthebleeding,sovitaminCmustbeusedwithcaution.
MALARIA
Oxidativestressisinvolvedintwowaysinmalaria.First,duringanacuteattackagreatdealofpro-oxidantfreeironisreleasedfromtheredbloodcellsdestroyedbytheparasite;second,thedefensivemacrophagesreleasemanyreactiveoxygenspecies.Stimulatingtheformationofnewbloodcellsrichinantioxidantenzymesisnecessarytoreplacethoselostduringseverehemolysisinseveremalaria.
Ontheotherhand,themalarialparasiteitselfisverysusceptibletooxidativestress.Thus,newpro-oxidantantimalarialdrugshavebeendevelopedbasedonthetraditionalChinesefolkmedicineqinghaosu.
Furthermore,adiethighinfishoilsrapidlyproducesavitaminEdeficiency,whichresultsinslowergrowthofthemalarialparasite;this,too,hasbeenusedintherapy.
MITOCHONDRIALDISEASES
Defectsinpartsofthecellcalledmitochondria,whichprovidetheenergythecellneedstofunction,manifestasmuscleandbraindisturbances.Anopentrialofantioxidants(whichincluded2GperdayvitaminCand400mgperdayofvitaminE)producedencouragingresults[163].Thepatients"appearedto"survive
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longerwithlessdisabilityandfewermedicalcomplications.Moreover,nosideeffectswerereported.Inanotherstudynicotinamide(theantioxidantvitaminB3)wasgiventogoodeffect.
MYOTONICDYSTROPHY
Thisdiseaseismarkedbyraisedplasmalevelsofreactiveoxygenspeciesandoxidizedfatsandloweredantioxidantdefenses.Notrialsofantioxidantmedicationhavebeenconductedasyet.
NEONATALOXIDATIVESTRESS
Birthresultsinoxidativestresstothenewborninfant,whopassesrapidlyfromalowoxygenpressureintheuterustoahighoneassoonasheorshestartstobreatheair.ArecentstudyofnewbornratscomparedtheinfantsofmotherratsgiventheantioxidantNACwithcontrols.Inthecontrolmotherratstheoxidizedglutathionelevelsinplasmaincreasedelevenfoldafterbirth;intheNAC-treatedgroupthelevelincreasedonlytwofold.Evidently,muchoftheactiveformofglutathionewasbeingdepletedbytheoxidativestressandconvertedintotheoxidizedform.ThisconversionwassloweddownbytheNAC.Humanstudiesinthisareaareawaitedwithgreatinterestbecausethebirthprocessisfraughtwithdangertoinfants,manyofwhomsufferbraindamageinwhichoxidativestressmayplayapart.Givingmothersantioxidantsinthelaterstagesofpregnancymayprotecttheinfantfromoxidativestressatbirth.
PANCREATITIS
Inflammationofthepancreasisoftenaresultofdigestionoftheglandbyitsownhighlypotentdigestivejuices.Thereare20,000casesofthissyndromeintheUnitedStateseveryyear.Insixteenoutoftwenty-fouranimalexperiments,antioxidantsalleviatedacuteexperimentalpancreatitis.Inhumans,fivestudieshaveshownthat
thisdiseaseisassociatedwithsevereoxidativestressanddepletionoftheantioxidantdefensesbeta-caroteneandvitaminsCandE.OneclinicaltrialofNAChasproducedpromisingresults.
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PREECLAMPSIA
Thiscomplicationofpregnancy,theleadingcauseofmaternalmortalityintheWest,ismarkedbyhighbloodpressureandedema(swelling).Inbothplasmaandcerebrospinalfluid,thetotalnumberofantioxidantsisabovethenormallevelsseeninuncomplicatedlabor.Thisismainlybecauseoftheraisedlevelsoftheplasmaantioxidanturicacid,togetherwithsomeasyetunidentifiedagents.Weightforweight,thepredominantantioxidantinbloodisuricacid,whereasinthecerebrospinalfluiditisvitaminC.ThereisalsoincreasedconsumptionofvitaminCbythebodybutnotvitaminE[93].SerumlevelsoftheantioxidantenzymeGSHpxaredecreased,togetherwithsignsofincreasedlipidoxidation[164].Oxidativestressmayplayaroleinpreeclampsia,butasjustoneofanumberoffactorsinvolved.
RENALDIALYSIS
Theredbloodcellsinpatientsundergoingdialysissufferoxidativestress,withreducedlevelsoftheantioxidantenzymesSOD,CAT,andGSHpx.Thisresultsintheredbloodcells'dyingbeforetheyshould,becausetheyhavemorerigid(andthusbrittle)cellmembranesandaresubjecttoincreasedfatoxidation.Antioxidantsaddedtotheperfusionfluidwouldbeexpectedtobeadvantageous.Anotherkidneyailment,glomerularnephritis,isassociatedwithoxidativestress[219].Undialyzedpatientswithchronicrenalfailureshowafailureintheirantioxidantdefensesthatworsensastherenalfailureincreaseswithtime[29];subsequentdialysisworsensthecondition,whichmayaccountforthehighrateofatherosclerosisinthesepatients.
RHEUMATOIDARTHRITIS
Thisisanautoimmunediseaseinwhichtheimmunesystemmistakesthejointliningsforforeigninvadersandproceedstolaunchanattack
uponthembyreactiveoxygenspecies.Thefluidintheaffectedjointsinthesepatientshaselevatedlevelsofreactiveoxygenspeciesandfreeiron.Themoreseverethediseasethehigheraremeasuresoffatoxidationintheblood.ManypatientswithrheumatoidarthritisaremarginallydeficientinvitaminsCandE.Alowbloodlevel
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ofvitaminE,beta-carotene,andseleniumisassociatedwithaneightfoldincreaseintheriskforthedisease[11].Panettaetal.oftheLillyResearchLaboratoriesarecarryingoutastudyofnewsyntheticdrugs,suchas4-thiazolidinone,whichhavepotentantioxidantandantiinflammatoryactionsinthisdisease[159].
SYSTEMICSCLEROSIS
Thisisaconnectivetissuedisease(alsocalledscleroderma)duetooverproductionofcollagenthatleadstovasculardamageandRaynaud'ssyndrome(repeatedattacksofvascularspasmleadingtogangreneoftheextremities).Itismarkedbyrepeatedischemiaandreperfusioninthetissueswithresultingoxidativetissuedamage.Manyorgansareinvolved,includingtheheart,lung,intestines,andkidneys.ThesepatientshavelowplasmalevelsofvitaminCbutnormallevelsofvitaminE.ItisnotclearifthelowplasmalevelsofvitaminC-duetoneitherdietarydeficienciesnormalabsorption-isacauseorresultoftheoxidativestress.Antioxidantsmightwellbeeffectiveinthisdisease.
TUBERCULOSIS
Theinterestingfacthasbeenunearthedthatthebacteriumresponsibleforthediseasehasadefectinoneofthegenesthatregulatesitsantioxidantdefenses.Thus,intuberculosis,thesedefensesarelow.Thisexplainswhytheoxidantdrugisoniazidissoeffectiveintreatingtheillness.Relatedorganismsthatdonothavethisdefectivegenearenotsensitivetoisoniazid.
clinicaldataonantioxidants
FLAVONOIDS
SOY.
Inseventeenoutoftwenty-fiveanimalstudies,genistin,acomponentofsoy,showedanticanceractivity.InChinaandJapan,wheresoyconsumptionishigh,therearelowratesofcancerofthebreast,prostate,andcolon.However,epidemiologicalstudieslookingatthecorrelation
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betweenhighsoyintakeandcancerratehavebeeninconsistent.Outoftwenty-sixstudies,tenreportedpositiveresults,fifteennoeffect,andoneanegativeeffect.Soatleastthebalanceisinthepositivedirection.
REDWINE.
Goldbergexpressestheopinionthat,ifwealldranktwoglassesofredwineaday,theincidenceofcoronaryheartdiseasewouldfallby40percent[69,70].However,drinkingwineinexcessmayleadtocirrhosisoftheliver,and''theuseofalcoholforcardiovascularpurposesshouldnotbeencouragedasapublichealthmeasure"[36].Moreover,alcoholitselfisapro-oxidant,andLDL(badcholesterol)ismoreeasilyoxidizedinbeerdrinkers.
Askepticalnotewasintroducedbyareportfromacountrywithhighbeerconsumption(Holland).DeRijkaetal.gavetwenty-fourhealthypeoplewithnormalbloodfatsredwinesupplementsforfourweeks[42].Thelevelofplasmaantioxidantsandfatswasunchanged.However,thistrialwasprobablytooshort.AcontraryreportstatesthatconsumptionofredwinedoesreducethesusceptibilityofLDLstooxidation[59].
TEA.
Inonestudyamixtureofantioxidantsfromgreenteahadapotentinhibitoryeffectonthegrowthofmammarycancersinrats.Astudyofover1oo,000peopleinHollandshowedthatconsumptionofblackteaformorethanfouryearsdidnotlowertheincidenceofstomach,colorectal,orbreastcancer.However,blacktea(butnotgreentea)alsocontainstannins,whichcanpromotetumors.Aprospectivestudyof35,369womenintheIowaHealthStudyfoundthattheintakeoftwocupsof"nonherbal"teaaday(equivalent,inamountofantioxidantstherein,toonehelpingoffruitorvegetables)wasrelated
toasignificant40to70percentreductionintheincidencerateoftwotypesofcanceronly-digestivetractandurinarytract[240].Theauthorsofthestudyquoteanumberofotherstudiesshowingprotectionbyteaagainstoral,pharyngeal,andnasopharyngealcancers.Theysuggestthattheflavonoidsinteamayblockthecancer-producingnitrosaminesintheintestines.Theyalsomentionthatthekidneymightconcentratetheflavonoids,whichwillresultinhigherurinarylevelsofflavonoidsandtherebyhelpinfightingtumorsintherenaltract.Theywarn,however,thatdrinkingteathatistoohotmightincreasetheriskofesophageal
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cancer.TheprotectiveeffectofthelargeteaconsumptioninJapanmayberesponsibleforlowerlungcancerratesintheJapanese,despitetheirhigherrateofsmokingthanAmericans'.AnepidemiologicalstudyinJapanreportedthatcancerpatientswhodrankmorethantencupsofgreenteaadayhadanincreasedlifeexpectancy(by4.5yearsformenand6.5yearsforwomen)ascomparedwithcancerpatientswhodrankfewerthanthreecupsaday[60].
InthecaseofcoronaryheartdiseaseastudyinWaleshadanegativeresult[87].Theinvestigatorsselected1,900malesinCaerphillyandfollowedthemforfourteenyears.Therewasnocorrelationbetweentheamountofblackteadrunkandtheincidenceofheartattacks.Infact,thosepeoplewhodrankmoreteahadanincreasedgeneralmortalityrate.
FurtherresearchshowedthatteadrinkinginWalesisassociatedwithalesshealthylifestyle(obesity,smoking),whichwastheprobablecauseoftheincreaseddeathrate-anexampleofaconfoundingvariableatwork.However,theWelshstudydidfindaprotectiveeffectofonions,whichalsocontainprotectiveflavonoids.
GARLIC.
LaboratorytestshaveshownthatgarlicextractsprotectLDLsagainstfatoxidationandhaveantiviral,antimicrobic,andanticancerproperties.Experimentsinanimalsshowthatgarlicextractsslowthedevelopmentofatherosclerosis[50].Garlicalsoprotectsagainstirregularitiesintheheartbeatandpreventsthedevelopmentoffattystreaksoncoronaryvessels(apreludetoatherosclerosis)inrabbitsfedlargeamountsofcholesterol.
Fiveepidemiologicalstudies(inChina,Italy,Poland,Australia,andtheUnitedStates)haveshownthatadiethighinalliumvegetables
(i.e.,garlic,onion,chives,shallots,etc.)thatcontainallicinandrelatedantioxidantsprotectedagainststomachandcoloncancerbutnotagainstbreastandlungcancer.
Inanexperimentalstudyofischemicbraindamageinrats,garlicextractreducedthesizeoftheresultingbraindamageandreducedbrainreactiveoxygenspeciesproductioninthetreatedratsascomparedwithcontrols.
Thebacterium(Helicobacterpylori)responsibleforgastricandduodenal(peptic)ulcersisverysensitivetotheantibacterialeffectofgarlic
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[200].Theauthorssuggestthatcasesofpepticulcerthatareresistanttotheantibioticsnowusedtotreatthediseasemightbenefitfromtheequivalentoftwosmallclovesofgarlicaday.
OLIVEOIL.
Trichopoulousuggeststhatoliveoilmayoffera"modestprotection"againstbreast,ovarian,andlungcancer,mainlybecause,inadditiontoantioxidants,itcontainsmonounsaturatedfats,whicharemoreprotectivethaneithersaturatedanimalfatsorpolyunsaturatedfatsfoundinmanyvegetablesources[218].
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part3thesafetyofantioxidantsandrecomendations
thefirstruleforphysiciansHippocrateslaiddownwas"Thoushaltdonoharm."Therefore,itisofprimeimportancethatwefindoutifantioxidantsareharmlessbeforeweprescribethemtoourpatients.Thefirstsectionofpart3examinesthisquestionindepth.Thesecondsectiondiscusseswhatkindofdietisindicatedbythedata,whetherpeopleshouldorshouldnottakesupplementsofantioxidantsinadditiontowhattheygetinthediet,and,iftheydotakethem,underwhatcircumstancestheyshoulddoso.
safetyofantioxidantsJusthowsafearethecommonantioxidantsincurrentuse?Opinionsvarywildlyfromthebeliefthattheyarecompletelysafetoprotestationsthatundercertainconditionstheycanbehighlydangerousandevenlethal.Whatfollowsaretheactualdataonthesafetyofantioxidantsandadiscussionoftheopinionsofferedbyvariousexperts.
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BETACAROTENE
Severalauthoritieshavejudgedbetacarotenetobesafeorminimallyhazardous.However,itisclearfromtheresultsoftheCARETandATBCtrialsreviewedabovethatbetacarotenesupplementsgivenbythemselvesshouldnotbeusedinsmokers,inwhomthesupplementshavebeenreportedtoraisethedeathratefromlungcancer,heartattacks,andotherconditions.Norshouldtheybeusedinpeoplewhohavehadaheartattack.Animalstudiessuggestthatbetacarotenecanalsoincreaseliverdamagecausedbyalcohol.Itshouldthereforebegivenwithcautiontopeoplewhodrinkalotofalcohol.Furthermore,raisingbetacaroteneintakelowerstheserumlevelsoftheimportantantioxidantcarotenoids,lutein,andzeaxanthin.Thisisespeciallyrelevantintheeyediseasemaculardegeneration(seethesectiononeyediseases),becausebetacaroteneisnotfoundintheretina,whereasluteinandzeaxanthinareessentialforproperretinalfunction.Givingbetacaroteneinthisconditionwouldtendtodeprivetheretinaofgettingtheluteinandzeaxanthinitneeds;thelattertwoshouldbeaddedtoanyvitaminsupplementformula.Anotherpointtonoteisthatcanthaxanthinsupplements,takeninlargeamountsforalongtime,cancausecrystalstoformintheretinathatinterferewithvision.Fortunately,thecrystalsareabsorbeduponstoppingthesupplement.
Theyellowingoftheskincausedbybetacaroteneisbenignandcompletelyreversible,andinanycaseitlooksmorelikeagoodsuntanthanjaundice.
VITAMINC
BecausePaulingmademegadosesofvitaminCnotorious,therehasbeengreaterconcernaboutthepossibletoxicsideeffectsofvitaminCtakeninlargedosesthanoftheotherantioxidants.Inmostpeopledosesupto500mgperdayseemtobeperfectlysafe,yettheremay
besomeexceptions.
Oneproblemisoxalatekidneystones.ThechiefmetaboliteofvitaminCisoxalicacid,themainingredientinthemostcommontypeofkidneystoneintheWest(80percent).Chalmersetal.gaveseventeenkidneystonepatientsandelevennormalcontrols2GperdayofvitaminCbymouth,andreportedthattheformergroupexcretedmoreoxalateandlessvitaminCintheirurinethandidthecontrols[30].Whenthe
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vitaminCwasgivenintravenously,thisdidnotoccur.TheauthorssuggestthatthestoneformersarenotabletoabsorbvitaminCaswellasnormalscan;vitaminCtakenorallythusremainsintheintestineslonger,formingmoreoxalate,whichisabsorbedassuch.TheyadvisethatpeoplewhoformoxalatestonesshouldnottakevitaminCsupplements.Urivetskyetal.,whosestudyoffifteenkidneystonepatientsgiven2GperdayofvitaminCrevealedatwofoldincreaseintheexcretionofoxalateintheurine,concludedthatthechronicadministrationofvitaminCsupplementsmadethemmoreliabletoformstones[220].Theyadvisethatsuchpeopleshouldnottakemorethan500mgperdayofvitaminC.RiversagreesthatvitaminCposesnoproblemtonormalpeople,butthatoxalatestoneformersshouldnottakevitaminCsupplements[177].Goldfarbdoesnotagreewiththis,contendingthatnormallythemetabolicpathwayfromvitaminCtooxalateisworkingatfullblastanyway,sothatanyincreaseinvitaminCintakedoesnotleadtoanyincreaseinoxalateexcretionintheurine[77].TheexcessvitaminCissimplyexcretedasvitaminCintheurine.However,inafewsusceptibleindividualsamarkedincreaseinurinaryoxalatecanfollowtheingestionof1-2GofvitaminC.Schmidtetal.gavefourpatientsaverylargedose(10Gperday)ofvitaminCandfoundthatthemeanoxalateexcretionincreasedfrom50mgperdaytoonly87mgperday[189].Theyconcludedthatthiswasequivalenttothemagnitudeofeffectthatasimplechangeofdietcouldproduce.Diplockstatesthatthe"stonestory"hasprovenoncriticalexaminationtobe"withoutfoundation"[44].IfexcessvitaminCisingested,itisexcretedassuch,notasoxalate.Heattributesearlierstudies'apparentfindingsthatincreasingvitaminCintakeledtoincreasedoxalateoutputtotechnicalerrorsintheestimation,suchasallowingtheurinetobecometooalkaline.Infact,heconcludesthatvitaminCinthedosesnormallyusedinsupplementsisentirelyfreefromsideeffects.CertainlyIhavenotseenanyreportsofacaseinwhichakidneystone,inreallifeas
opposedtotheory,couldbetracedtovitaminCsupplements.Nevertheless,highdosesofvitaminCshouldbegiventoknownoxalatestoneformerswithcautionandonlyatthediscretionoftheindividualphysician.
AnotherpossibleproblemwithvitaminCisthat,inthepresenceoffreeiron,itbecomesapro-oxidantandshouldthereforenotbegiventopeoplewhomayhavefreeironthatmightreactwiththevitaminC.
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Normally,ironinthebodyissafelystoredinsidevariousproteins,andfreeironlevelsareextremelylow.Thisisjustaswell,asfreeironisexceedinglytoxic.Itthuscausesnoproblemsinthisregardinnormalpeople.Butsomeexperts(particularlyHerbert[83-851)advisethatvitaminCsupplementsnotbetakenbypatientswithironoverload,asinhemachromatosis,sideroblasticanemia,andthalassemia.HerbertsuggeststhatvitaminCsupplementsshouldnotbetakenifthebloodlevelofferritin,aniron-bindingprotein,isover120µg/L.Incontrast,otherauthoritiesstatethatironisalwayssafelyboundtoprotein;sovitaminCinfact,asopposedtotheory,neverinteractswithfreeirontoproducepro-oxidanteffectsinreallife[14,38,45,147].HerbertreferstoasubmissionpapermadebyM.KrikkertoanFDAcommitteethatmentions"severaldeathsinathletesduetothiscause."Iamnotawareofanysuchinteractionreportedinanyscientificpaper.HealsostatesthatpatientsinastudyontheeffectsofvitaminConcancerbyMoerteletal.[145]attheMayoClinicdid"muchworse"onvitaminC.Ihavereadthelatterpaperandwasunabletointerpretitinthisway.Infact,theMayoClinicgrouptreated1ooterminallyillcancerpatientswith10GperdayofvitaminCforuptoeighteenmonths(averagefourmonths)butthetreatmenthadnoeffectofanysort,goodorbad.ThestudywascarriedouttorefutetheclaimmadebyCameronandPaulingthatlargedosesofvitaminCproducedmarkedbenefitinsuchcases.Moerteletal.cametotheconclusionthatthisclaimwasbasedonasimpleerrorinthedesignofthetrial[145].DailyandZemel,inaneditorialintheAmericanJournalofClinicalNutrition,characterizeHerbert'scontributiontothedebateas"polarizinghyperboleandgrandstanding....WhatiscertainisthatthecontinuingdebateisnotwellservedbybeingreducedtothetypeofdiatribeevidentinHerbert'scommentary"[37].InapaperreadtoameetingoftheOxygenClubofCalifornia,GladysBlockpresentedevidencetoshowthatvitaminC,eveninthepresenceoffreeironinlivinghumans,actuallyinhibitsfatoxidation.
However,BartonandBertolipointout(asHerberthasclaimedovertheyears)thathemachromatosisisamuchmorecommondiseasethanisgenerallyrecognized[10].OnemillionAmericansarehomozygousforthegeneresponsibleandoneineightofthepopulationareheterozygous.Ironoverloadproblemsarecommonlyclinicallyoverlookedand
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screeningtests[49]shouldbemuchmorewidelyused[10].Suchtestswouldthereforeseemtobeadvisablebeforeadoctor'srecommendinghighdosesofvitaminC.
ThereareconflictingreportsastowhethervitaminCsupplementsmayinduceorimprovecataractsinelderlypatientswithdiabetes.Inmostpeople,aswesawearlier,vitaminCappearstoprotectagainstcataractsandagainstdiabetes.Elderlydiabeticsmayproveanexceptiontothisrule.
Toavoidhemolysis,vitaminCshouldnotbegivenintravenouslytopatientswithaconditionknownasglucose-6-phosphatedehydrogenasedeficiency[122].BendichandLangsethstatethatsomepreviousanecdotesclaimingtheallegedtoxicityofvitaminChavebeenexaggerated[12].IncontrolledtrialsithasbeenshownnottodestroyvitaminB12,itisnotmutagenic,itdoesnotcausereboundscurvyorabnormalpsychologicalreactions,anditdoesnotimpaircopperutilization-allofwhichhadbeenclaimedpreviouslyonananecdotalbasis.However,itcaninterferewithanumberofclinicalandlaboratorytests[143],includingbloodleveltests.Thetestsforglucose,uricacid,creatinine,alkalinephosphatase,andinorganicphosophategivefalselyhighlevels.Thetestsforbilirubin,lactatedehydrogenase,carbondioxide,potassium,catechol-o-methyltransferase,monoamineoxidase,cholesterol,creatinekinase,anddopa-ß-hydroxylasegivefalselylowlevels.Thetestforoccultbloodinfecesgivesafalsenegativeresult.Testsforacetaminophengivesfalsepositiveresults.AnumberoftrialsoflargedosesofvitaminC(forexample,thosebyPaolissoetal.[160],whogave1Gperdayforfourmonthstoforty-ninepeople;Busseyetal.[25],whogave3Gperdayfortwoyearstoforty-ninepeople;andMcKeowen-Eyssenetal.[136],whogave400mgperdayfortwoyearstoninety-sixpeople)havereportednosignificantsideeffects.
InanimalexperimentsvitaminCcanhaveeitheranticancerorcancer-promotingeffects,dependingoncircumstances.VitaminCdepressesDNA,RNA,andproteinsynthesis(i.e.,cellgrowthanddivision)insomecancer(neuroblastoma)cellsthathavehighironlevels,butitdoesnotdosoinnormalcells.ThehighironlevelscausethevitaminCtohaveapro-oxidanteffect.ThissuggeststhatvitaminCmightbeapowerfulenhancerofsomeantitumordrugsusedinthetreatmentofneuroblastoma.VitaminCcausesDNAdamageinneuroblastomacellsbutnotnormal
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cells.Benzathione(apowerfulcarcinogen)toxicityinguineapigsisreducedbyvitaminC.
Inonestudy,whereasanantioxidantmixtureofbeta-carotene,vitaminsCandE,andglutathionewaseffectiveinpreventingtheproductionoforalcancersbycancer-producingchemicalsinhamsters,vitaminCgivenbyitselfactuallyincreasedthecancerrate[194].TheresearcherssuggestedthisresultmightbeduetotheproductionoftoxicderivativesofvitaminCthatarenormallymoppedupbyvitaminEandtheotherantioxidantsinthemixture.Withoutthismopping-upoperation,vitaminCbyitselfprovedtobeharmful.Thisresultstressesonceagaintheenormousimportanceoftheteamactionoftheantioxidants.ThisisfurtherstressedbyPrasadandKumar,whostatethatmultipleantioxidantadministrationisessentialforthemaximumreductionofcancerincidenceinahigh-riskpopulationandthattheuseofjustoneortwoantioxidantsislikelytobeineffectiveandevenharmful[165].
However,astudybyJacquesetal.suggeststhatthisisnotanabsoluterule[96].TheymeasuredtheeffectsonbloodlevelsoftheraisedintakeofonlyoneofeithervitaminC,vitaminE,orcarotenoids;givingonlyoneledtoraisedbloodlevelsofoneorbothoftheothertwowithoutanyimpairmentofantioxidantstatus.Theyexplainedthisresultbypostulatingvariousinteractionsbetweenthedifferentantioxidantsatseverallevelsduringthepreparationoffood,inthegastrointestinaltract,inthecell,andbysparing.Forexample,theraisedvitaminClevelmayconvert,byitssynergisticaction,moreinactivatedoxidizedvitaminEtotheactiveformofvitaminE.
VITAMINE
ThereareonlytworecognizedcomplicationsofvitaminEtherapy.Thefirstisthatitcanworsenthecoagulationdefectcausedbyvitamin
Kdeficiency,whichisdueeithertomalabsorptionofvitaminKfromtheintestinesortoanticoagulanttherapy.Thesecondisthat,whereasvitaminEcertainlylowersbloodplateletcounts,thismaynotalwaysbebeneficialincertainpeople,asitmayincreasetheriskofhemorrhagicstroke.Therefore,solongasthesearerecognized,vitaminEtherapyisconsideredsafebymostauthorities[53,138,187,226].ByersandBowman,however,worryaboutpossibleasyet
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unknownsideeffectsoflong-term,high-dosevitaminEtherapy[26].ThisworrydoesnotseemtobejustifiedinviewofthefactthatmanyhundredsofthousandsofpeoplehavetakenvitaminEsupplementsoverthelastdecadewithoutanyreportsofsuchcomplications.However,raisingthelevelofintakeofalpha-tocopherol(vitaminE)lowersthelevelofitscloserelativegamma-tocopherol.Gamma-tocopherolismorepotentthanalpha-tocopherolindetoxifyingnitrogendioxide(thepotentoxidantinsmogandcigarettesmoke);thus,gamma-tocopherolshouldbeaningredientinanyantioxidantprogram.
recommendationsWhatconclusionscanwedrawfromthismassofdata?Giventhatmanyoftheinvestigationsandexperimentshavehadcontradictoryandconfusingresults,clearlymuchmoreworkneedstobedonetoclearupsomeoftheissues.However,certainthingshavealreadybeenclearlyestablished.
Itcannowbetakenasafactthattoxicreactiveoxygenspeciesplayasignificantroleinmanyacuteandchronicdiseasessuchasinflammation,coronaryheartdisease,cancer,diabetes,cysticfibrosis,rheumatoidarthritis,Alzheimer'sdisease,Parkinson'sdisease,andmanymore.Furthermore,theyplayanimportantroleinmanynormalbodilyprocesses,suchascontrolofgeneexpression,immuneresponses,controlofbrainsynapses,theactionofwhitebloodcellsinkillingbacteria,andothers.Wenowknowquitealotaboutthenatureofthebody'sdefensesagainstreactiveoxygenspecies.Morethantwentyimportantantioxidantsystemsinthebodyhavebeenidentified.
Itisalsonowbeyonddisputethatahealthydietshouldbedesignedto
haveaplentifulandvariedsupplyoffruitsandvegetables,aswellasaproperattentiontotherightandwrongsortsoffat,reducedsalt,andalowalcoholandlowcalorificintake.However,eventoday,ithasbeenestimatedthatonlyopercentoftheU.S.populationfollowthisadvicewithregardtofruitsandvegetables.Dietaryhabitschangeslowly.Inmanyareasfruitsandvegetablesareexpensive,andsomepeoplecannotaffordthem.ManyrestaurantsintheUnitedStatesaredieteticdisasterareas,withredmeat,saltypotatoes,andbutterybreadsasthestaplefoods.InSanDiego,California,theYellowPageslistonlyeightvegetarianrestaurants.
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Inhomekitchensmanyvegetablestendtobeovercooked,whichdestroystheirvitaminC.Howmucheasiertobuyabottleoftabletslabeled''antioxidantvitamins"andtrustthatwilldothetrick!
Furthermore,thegeneralpubliciscurrentlymuchconfusedbyallthecontradictoryreportsthathavebeenpresentedbythemedia.Onedaybetacaroteneisin,thenextitisout.Onedaymargarineisrecommendedinsteadofbutter;thenextdayadifferentadviceisgivenfollowingtentativeresearchreportsbyscientists.Manybookswrittenforthegeneralpubliconthistopicareuncriticalandmisleading.
Asitisnowclearthatantioxidantsworkasateam,itispointlesstodesignlargeandexpensiveclinicaltrialsofjustoneortwooftheantioxidants.Theantioxidantmixturetobetestedshouldcontainalltheprominentantioxidants,bothwater-solubleandfat-soluble,variouscarotenesandflavonoids,andpossiblyagentsdesignedtoraiseglutathionelevelsinthebody.
Mostexcessmineralsaddedtothesupplementaresimplynotabsorbed,exceptincasesofmineraldeficiencyfromthepreviousdiet.Seleniumisanexception,butseleniumoverdosageistoxic.However,calciumandmagnesiumarebeneficentevenwhennotabsorbed,astheyformveryinsolublesaltswithdeleteriousfattyacidsintheintestinesandsopreventtheirabsorptionfromtheintestines.Thismayhelptopreventcolorectalcancer.Calciumisalsorequiredbysomepeopletoguardagainstosteoporosis.
Furthermore,thereisnowaverystrongcasethatantioxidantsareneededinthemedicaltreatmentofspecificconditionssuchasischemia/reperfusion,acutemyocardialinfarction,asthma,shock,ARDS,cysticfibrosis,diabetes,Alzheimer'sdisease,andsoon.FurtherresearchmayadddiseaseslikeParkinson's,schizophrenia,ALS,andAIDStothislist,astheevidencealreadylookspromising.
Thepresentmajordisagreementcentersonwhetherantioxidantsupplementsshouldberecommendedforthegeneralpopulationinanattempttowardoffthedevelopmentofchronicdiseasessuchasheartdisease,cancer,cataract,andParkinson'sdisease.Inotherwords,shouldweraisetheRDAsforthekeyantioxidantvitamins?
Thefollowingisanaccountofthemostup-to-daterecommendationsmadebyrecognizedexpertsinthefield,beginningwiththosewhoadviseagainstraisingthepresentRDAs.
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MeyersandMaloleyrequire"clearproof"ofefficacyandthelackoflong-termtoxicitybeforetheycanrecommendsupplementsofvitaminsCandE[143].Theymaintainthatmanyoftheresearchreportsthatsuggestthatsuchsupplementsareneededareflawedbynottakingintoaccountotherriskfactorsforheartdiseaseandothercomplicatinghealth-consciousbehaviors(healthylifestyles)bythesubjects.However,aswehaveseen,manypositivetrialscannotbeexplainedonthehealthy-lifestylehypothesis.MeyersandMaloleyestimatethat,inspiteoftheiradvice,some25percentofAmericansself-medicatewithvitaminsupplementsonaregularbasis.
IllingworthagreeswithMeyersandMaloleyandoffersthiscaveat:"Intheabsenceofmoreconvincingclinicaltrialdataitseemsprematuretoadvocatesupplementationwithantioxidantvitamins[topreventcoronaryheartdisease]exceptinselectedhighriskpatients"[94].
Oliversays"thereisasoundscientificbasisandrationaleforincreasingtheintakesofvitaminEandCtoreduceoxidationofLDL"topreventcoronaryarterydisease,butheconcludesthatitisstilltooearlytorecommendsupplements."Thebestpossibleadvice"istoeatfoodshighinvitaminsCand/orE,includingcerealoils,nuts,freshcitrusfruits,freshvegetables,andpotatoes-manyofwhichareexpensive[151].Potatoes,whichareaffordable,arelackinginantioxidantsotherthanvitaminC,andfoodsourcesrichinEareallfatty.
RautalahtiandHuttunenofFinland'sNationalPublicHealthInstitute,Helsinki,adviseagainstantioxidantsupplementsforthepreventionofcancerbecauseofthelackofagreementintheclinicalresearchbase[171].However,thetrialstheymentionarehardlyafairselectionofthedatabase.Theyselecttwonegativetrials,oneinmelanomaandtheothertheflawedATBCtrialinFinland,wherewehaveseenthat
inadequatedosesofsyntheticvitaminEwereusedinthehopelesstaskoftryingtorollbacktheeffectsofheavycigarettesmokingoverhalfalifetime.ThepositivetrialtheyciteistheLinxiantrialinChina,inwhichthesubjectswerenutritionallydeprivedanyway[18].Theyshouldhaveusedabetterandwiderdatabase.
Maxwell[132]andHoffmanandGarewal[90],inreviewsofatherosclerosis,saythatthoughresearchtodatehasyieldedpromisingandexcitingresultstheycannotadvocateantioxidantsupplements-againlargelyonthebasisoftheflawedATBCtrial.
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Diplocksaysweneedtolookatthreelevelsofevidence[143]:
1.epidemiologicalstudiesoftherelationbetweenlevelsofintakeofnutrientsanddiseaserates,
2.prospectivestudiescomparingplasmalevelsofnutrientsanddiseaserates,
3.double-blind,placebo-controlledinterventiontrials.
Heconcludesthatthereisampleevidencefromlevels1and2tolinkantioxidantsandcoronaryheartdiseaseandsomeformsofcancer.Butthereisasyetlittleevidencefromlevel3.
ThedisagreementamongdoctorsonthismatteriswellillustratedinthepagesofthetwentietheditionoftheprestigiousCecil'sTextBookofMedicine,publishedin996.Inhischapterentitled"CancerPrevention,"GilbertOmennhardlymentionsantioxidants.InhisdiscussionofdiethementionsonlytheroleoffatandfiberandignorestheextensiveliteratureIhavequotedontheroleofantioxidants.Inhisdiscussionoftestsofsupplementsofantioxidantvitaminsincancer,hementionsonlytheFinnishATBCtrial,butnotitsmanydefects.Incontrast,WilliamBlot,inhischapteron"TheEpidemiologyofCancer,"givesprominencetotheroleoffruitsandvegetablesandsaysthatcarotenoidsaswellasvitaminsCandEcanreducetheriskofgettingcancer.JoelMason,inhischapteron"ConsequencesofAlteredMicronutrientStates,"alsostatesthatbeta-caroteneandvitaminEareprotectiveagainstsomecancers.RolandWeinsier,inhischapterondiet,statesthat"unprescribeddailyuseofsupplementsinamountsexceedingtherecommendeddailyallowanceshouldbeavoided.''Iagreeherewiththeword"unprescribed."Thecomplexitiesofantioxidanttherapyaresuchthatitshouldnotbeusedwithoutmedicaladvice,asIexplainlaterinthissection.
Argumentsfortheotherposition-thatRDAsshouldbechangednow
andthatantioxidantsupplementshaveaplaceintreatment-havecomefromsomeequallyeminentauthorities.
InaneditorialintheJournaloftheAmericanCollegeofNutrition,Blumbergexpressesthecontrarypositionforcefully[19]:"Itisunrealisticandunnecessarytowaituntiltheclinicaltrialsarecompletebeforeapplicationsfordiseasepreventionareendorsed."Hesaysthattheevidenceshouldbejudgedintotoandnotjustonthestandardsappliedto
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newdrugs-thatis,prospective,randomized,double-blind,placebocontrolledtrials.Healsocommentsthatantioxidants"appearremarkablybenignevenathighsupplementaryintakes"andthattheyareinexpensivetoboot.Heconcludes:"Recommendationtowaituntileveryconceivablestudyhasbeendesignedandconductedtoachievealevelofabsolutecertaintywillresultinthecontinuingcostofthediseasetotheindividualandsociety."
GeyagreesthatanupdatedprudentdietshouldcontainmorethanthecurrentRDAsofvitaminsCandEandbeta-caroteneplussupportingplantantioxidants[64].TheintakeofvitaminCneededtopreventscurvyis1mgperkgofbodyweightperday,whereasmostotheranimalsmakevitaminCatamuchhigherrate(40-275mg/kg/day,or3-19G/dayforahumanweighing70kg!).Moreover,ithasbeenestimatedthatourStoneAgeancestors,wholivedbyhuntingandgathering,hadavitaminCintakeofabout325mgperday.ItisthereforelikelythatevolutionhasproducedahumanbodythatneedsthisamountofvitaminC.
Mehraetal.state,"Itshouldberecognizedthat'definitivedata'isoftennotavailabletosupportalldecisionsinmedicalpractice"[138].Theyroutinelyrecommendantioxidantsupplements(beta-caroteneandvitaminsCandE)fortheprimaryandsecondarypreventionofatherosclerosis.Buttheystressthatthisisnotasubstituteforarigorousprogramofreductionofalltheotherknownriskfactors.Leskeetal.givesimilaradviceforcancerprevention[121].WeisburgeroftheAmericanHealthFoundationsaystheconceptofRDAs,withitsfocusontheavoidanceofdeficiencydiseases,isoutofdate[231].Hesaysthatitshouldbereplacedbythenewconceptofoptimalnutritiontoavoidchronicdiseasesandtoprotectagainstenvironmentaltoxins.ByersandBowmansay"betterdietaryadvice,possiblefortificationoffoodsupplies,andtheuseofrationallyformulatednutritionalsupplementsmaysoonemergeaspublichealth
strategiestohelppreventchronicdiseases"[26].
However,optimallevelsofintakehaveyettobedefined.OnthispointTengerdysays,inthecaseofvitaminE,thattheoptimumdosedependsonmanyfactorsandneedstobedeterminedforeachperson[215].Inparticular,becauseofthedemonstratedeffectofvitaminEinboostingimmuneresponses,herecommendsvitaminEsupplementationforthreetofourweeksbeforevaccination,providedthebloodlevelofthevitamin
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ismonitoredandanadequateseleniumintakeisassured.An"updatedprudentdiet,"accordingtoGey,shouldcontainImgofvitaminA,6-15mgofbetacarotene,60-250mgofvitaminC,and60-100mgofvitaminEsupportedby"plantantioxidants"[64].ToxiclevelsareestimatedbyVanderHagenetal.asover150,000IUforbetacarotene,1GforvitaminC,800mgforvitaminE,and500µgforselenium[221].Theseauthorssupporttheuseofsupplementsforthepreventionofeyedisease.BarberandHarrisadvisethefollowinglevelsofintakeofantioxidants:betacarotene15-30mg;vitaminC100-500mg;vitaminE200-800mg;selenium1o-1ooµg[9].Hathcocksaysthattoinhibittheformationofcancer-producingnitrosaminesinthestomachcompletely,oneneeds1GperdayofvitaminC[80].HealsonotesthatveryhighlevelsofingestionofvitaminCcansuppresstheabsorptionofcopperandthathighlevelsofzincingestion(100-300mgperday)canraiseLDLandlowerHDLlevels.
Inresponsetothosewhorecommendrelyingentirelyongettingpeopletochangetheirdiet,Johnsonsaysthatexperiencedcliniciansknowthatpeoplerarelychangetheirdietaryhabits;therefore,thisapproachis"likelytobetheleastacceptable,orpossible,orsuccessfulformanyhigh-riskindividuals"[98].ThissentimentissupportedbyWeisburger,whorecommendsvitaminsupplementationforpeoplewhodonot,willnot,orcannotaffordtoeattheirthreeservingsofvegetablesandtwooffruitaday[230].
Levineetal.pointoutfiveflawsinthecurrentmethodfordeterminingtheRDAofvitaminCandlisteightcriteriaastohowitshouldproperlybedone[122].TheystatethatthecurrentRDAsdonotreflecttheoptimumdosage,butwedonotyetknowenoughtosayexactlywhattheoptimumamountshouldbe;theysuggestprovisionallybetween200-500mgperdayofvitaminC,asmuchaspossiblefromfruitsandvegetables.Aswesawearlier,thedietofour
Paleolithicancestorshasbeenestimatedtocontainaround325mgofvitaminCperday.Themaximumamountobtainablefromanormaldietisaround500mgperday.
AnimportantpaperbyLevineetal.providesthestrongestevidencetodatethattheRDAforvitaminCshouldberaised[123].TheystudiedsevenhealthyvolunteersoversixmonthsonvariousdosesofvitaminC-
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from30to2,500mgperday-andmeasuredhowmuchvitaminCinthedietisneededtoobtainamaximumbloodlevel.TheyfoundthatthepresentRDAof60mgperdaydoesnotdothis;1oomgperdayarerequiredtosaturatethebloodcells(redandwhite),whichshowaconcentrationfourteentimesthatofplasmalevels.But200mgperdayareneededtoachievesatisfactoryplasmalevels.SotheyrecommendthattheRDAforhealthyyoungmenberaisedto200mgperday.Theystatethatanyintakeover500mgperdayissimplyexcretedintheurineandthereforewasted,butthatlevelsupto1Gperdayaresafe;abovethatleveloxalateanduratelevelsintheurineincrease.However,theystressthattheserecommendationsapplyonlytohealthyyoungmen;differentlevelsmaybeneededforwomen,smokers,thesick,andtheelderly.
Blockhaspublishedacogentcriticismoftheorthodoxviewthatonlydouble-blind,placebo-controlledtrialscansupplytheanswertothisquestion[16].Listingaseriesoffallaciesinthisapproach,shesaysthesetrialsusually:
selectpersonsathighriskforadisease;
rarelytestmorethanoneortwosubstancesandusuallyatasingledose;
testonlytheefficacyofanagentgivenforalimitedtime,usuallylateinlife;
telluslittleaboutpreventionoflong-termchronicdiseases;
tellusnothingaboutwhethertheagentathighdosemightreducetheriskofchronicdiseasesiftakenthroughoutalifetime;
tellusnothingaboutthecombinationofantioxidants,whichwehaveseentobesoimportant;
donothingtoresolvethequestionsthatinterestus,whichinvolve
personswithnounusualriskofdisease,alifetimeexposuretonoxiousandprotectiveagentsinvolvinganenormouslycomplexinteractionamongnutrients,andtheeffectsofthesenutrientsonhundredsofdiseases,manyuncommon.
Clinicaltrials,shesays,simplycannotanswerthesequestions.Whatweneedisasolidexaminationofthelaboratoryandepidemiologicalevidence.
Myadditionalcommentsarethatmanypresent-dayrecommendationsapplyonlytopeoplenotunderoxidativestress,thattheydonotaddress
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thequestionofteamworkbetweenantioxidants,andthattheydonotconsiderthepossiblepreventionofanumberofchronicdiseasesasopposedtoonlyone.Furthermore,iftheintakeofvitaminEisraisedto400-800mgperday,thenmorevitaminsCandB3(nicotinamide)willbeneededasavitaminEhelpers.
DraperandBettgersaythatthequestionofwhetherRDAsshouldberaisedisapharmacologicalmatterandnotonefornutritioniststodiscuss[45].Florenetal.placetheresponsibilityontheindividualphysician,whoshouldrelyonhisorherclinicaljudgmentastowhethertoprescribevitaminsupplements[56].Thetroubleisthatmanycliniciansdonothaveaccesstoreliableinformationonwhichtobasetheirclinicaljudgment-thatgapbeingoneofthisbook'sintentionstofill.
A1997surveybasedinNewOrleanswasmadebyaquestionnairethataskedcardiologistsiftheytookantioxidantsupplements[139].Forty-fourpercentofthosewhorespondedtothequestionnairesaidthattheydid(inthedailyrangeof400mgofvitaminE,500mgofvitaminC,and20mgofbeta-carotene).Ironically,only37percentofthemsaidthattheyrecommendedthesesupplementsfortheirpatients.
Anewapproachisnowbeingexplored:howtoenrichourfoodwithantioxidantandprotectiveagents.Thesimplerapproachistoaddantioxidantvitaminstobasicfoods.Studiesaddressthegeneticengineeringoffoodtopreventheartdiseaseandcancer[105],andsuchmeasuresasgrowinggarlicwithseleniumfertilization[95].Theauthorsofthesestudiesstatethat"inviewoftheimpossibletaskofpersuadingthepublictoeatonlythosefoodsthatarepresumablygoodfortheirhealth...thetimehascometoenrichourfoodswithknowncancerpreventiveagentssothattheirbenefitcanberealizedfullyoverthelifespanoftheindividual"[95].Theirgloomyestimationofthepotentialtopersuadethepublictoimproveitsdietis
supportedbyastudyofanintensive,two-yeareducationalandexhortationcampaigninwhichinvestigatorsoperatedfromaselectedsupermarket.Theyhadonly"modest"resultsingettingthesubjectsoftheexperimenttobuymorehealthyfoods.Themainimprovementlayinincreasingthepurchaseoffruitsandvegetables.Measurementofanyfurtherchangesinnutritionalknowledgeandattitudesshowedonly"mostmodest"improvements[179].
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conclusionsInspiteofthemanydisagreementsintheliteratureoverdetails,thetotalevidencefromallsourcesseemstoindicatethatantioxidantscanplayaroleinthepreventionandtreatmentofmanydiseases.Moststudiesreportpositiveeffectsinsomeareaseveniftheydonotagreeonthedetails.Thereareveryfewreportsofactualharmfulresultsofgivingantioxidants-infactasopposedtotheory.Inthosethatdo,thecauseoftheharmfulresultisusuallyclearandcanbeavoided.
However,themainproblemremains,whetherweshouldrelyondiet,orsupplements,oracombinationthereof.Obviously,inthebestofallpossibleworldsthebestsolutionwouldbediet,withtheprovisothatvitaminEsupplementsshouldbetakensothatapersoncanavoidconsumingtoomuchfatfromvitaminE-richfoods.ThisinturnrequirestakingenoughvitaminEhelpers,suchasvitaminsB3andCandselenium.IdonotseehowanyonewhohasstudiedthedataonvitaminEinthepreventionofheartdisease(giveninpart2)couldfailtorecommendthattheRDAforthisantioxidantvitaminberaisedtoatleast400mgperday.Thewell-conductedinvestigationswithpositiveresultsshowingtheprotectiveroleofvitaminEcannotsimplybeignored.AgoodreviewofthistopichasbeengivenbyWeberetal.[228].Furthermore,adiethighinfruitsandvegetablesdoesmorethanprovideantioxidants.AsWisemanandHalliwellsayintheirreview,"itwouldbenaiveintheextremetoassumethattheprotectiveeffectsoffruitsandvegetablesarerelatedonlytotheirantioxidantcontent"[234].Otherimportantfactorsincludeantiangiogenesisfactors,inducersofenzymesthatcombatcarcinogens,fiberandphytates,aswellasareductionoftheintakeoffatandiron.Ontheotherhand,someantioxidantsmayinfactexertsomeoftheirbenefitsbymeansotherthantheirantioxidanteffect-forexample,thelikely
actionofvitaminCinmoppingupcarcinogenicnitrosaminesinthestomach.
Furthermore,thesimpleadmonishmenttoeatmorefruitsandvegetablesisnotenough-whichfruitsandvegetables?Again,prudentadvicewouldbeawidevariety,includingsourcesofcarotenes(carrots,apricots,spinach,redandyellowpeppers,andcollardgreensforbeta-carotene;darkgreenleafyvegetablesforluteinandzeaxanthin;tomatoesandpeanuts
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forlycopene);offlavonoidsandpolyphenols(onions,greentea,oliveoil,redwine,peanuts,coffee,chocolate,oranges,licorice,andmanyothers);ofvitaminE(nuts,grains,margarine,mayonnaise,wholewheatgerm,darkgreenleafyvegetables);andvitaminC(potatoes,citrusfruits,andothers),togetherwitholiveoilwheneverpossible,garlicandshallots(forallicins),andthespicesandherbslistedearlierthatcontainarichvarietyofantioxidants(seetheappendixformoredetails).NotethatpotatoesdonotcontainsignificantamountsofantioxidantsotherthanvitaminC.
Healthauthoritiesneedtomountamuchmorevigorouscampaigntoinformthepublicoftheenormousimportanceofamassivenationwidechangeineatinghabits,inparticularwithregardtofruitsandvegetables.ItissomewhatdepressingthatPattersonetal.madepreciselythissamepointin1990[162].TwoyearslaterBlackburnpointedoutthatthefruitandvegetableindustryhadshowedlackofleadershipbyfailingtopromotetheirwares(exceptforavocados,prunes,raisins,andbananasnoneofwhichcomeatthetopofourlistofhealth-promoters)[15].Healsocalledforanationalcampaign(whichhasfailedtomaterialize).Heestimatedthepotentialsavingofsome$150billionayeariftheU.S.dietcouldbeimprovedsimplytoconformtopresentofficialrecommendations.TheNationalCancerInstitutehasstartedaprojectinconjunctionwiththeagriculturalindustrywiththeaimofincreasingpeople'sfruitandvegetableintake.
ApaperfromSouthAfricaentitled"PublicNutrition:WhoIsListening,Responding,andActing?"makesevenmoredepressingreading[226].Init,Walkermakesthefollowingpointsbasedonasurveyofthecurrentliterature:
Themajority(90percent)ofthepublicintheUnitedStates(andmanyotherindustrializedcountries)donotfollowofficialnutritionalguidelines.
Therehasbeennoreductionintheintakeofcalories,totalfat,andsaturatedfat.
Theconsumptionoffruitsandvegetableshasnotincreased.
Poorpeoplecannotaffordenoughfruitsandvegetables.
InmanydevelopingcountriespreviouslyhealthydietsarebeingreplacedbytheinjuriousWesterndiet.
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OfsevensurveysinvariouscountriesofthehealtheffectsofthedietduringtheWorldWarIIperiod,allshowedareductioninobesity,diabetes,coronaryheartdisease,anddentalcaries.Duringthatperiodtherewasaprofounddecreaseintheconsumptionofanimalfats,sugar,andmeat.Consumptionofmanybasicvegetablesrose.Obesityanddiabetesarecurrentlyontheincreaseamongmanysegmentsoftheworld'spopulation.
Currenttelevisionadvertisingbythefoodindustryconcentratesontryingtosellfoodhighinfat,sugar,andsaltandisparticularlyaimedatchildren.
Parentsneedtoredoubletheireffortstogettheirchildrentoeatfruitsandvegetables,which,forsomeunfathomablereason,manyofthemseemtodetest.Furthermore,howmanydoctors,whotreatcommonchronicdiseases,activelyencouragetheirpatientsandtheirpatients'familiestofollowthissoundnutritionaladvice?AstudyinMassachusettsofprimarycarephysiciansfoundthattheamountofdietaryadvicetheygiveisactuallydeclining[227].Theresearcherssaidthatthiswasprobablyowingtothelackofvalidandconsistentdatapresentedtosupportmanyofficialdietaryrecommendations.OtherstudiesofprimarycarephysiciansinAustraliaandHollandhaveshownthattheirdifficultiesaroseforseveralreasons.Thesephysiciansfeltuncertainastowhethertheywereentitledtointerfereintheirpatient's"lifestyles"unlessaskedtodoso.Theyreflectedtheemphasisinmodernmedicineoncureratherthanpreventionandconfessedtoalackofknowledgeofthefield,lackofconfidenceintheirexpertiseonnutritionalissues,andlackoftimetodiscussthesemattersduringabusyclinicalpractice.
Onepotentreasonwhythepublicdoesnottaketheadvicetoeatmorefruitsandvegetablesseriously,Isuggest,isthefailureoftheauthorities(suchastheFoodandNutritionBoardoftheNational
AcademyofSciences)toraisetheRDAsofantioxidantvitaminsandrelatedsubstances.AdvicetothepublicmustbebackedupbystatementsfromtheNationalResearchCouncil,theNationalAcademyofSciences,theFDA,theSurgeonGeneral,andothersimilarbodiesexplainingthatpeopleshouldtakemoreantioxidantvitaminsthanjusttheminimumamountneededtopreventvitamindeficiencydiseasesinviewofthenowoverwhelming
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evidencethatantioxidantvitamins,andantioxidantsingeneral,domuchmorethanthat.Healthofficialsmustalsothenurgepeopletoobtaintheirvitaminsandantioxidants,asfarasispossible,byimprovingtheirdiets.Onegroupofferinghealth-relatedpronouncements,theAllianceforAgingResearch,hasinfacturgedthattheRDAsberaisedimmediately.
Concedingthatmanypeoplewillstillnotfollowgoodadviceaboutdiet,weneedtoadvisethenextbestthing,whichistotake,undermedicalsupervision,abalancedsupplementregimencontainingaswideavarietyofsynergisticantioxidantsascanbeobtained.Medicalsupervisionisadvisableforthesereasons:Apersonmayhaveaconditionsuchasironoverload,orbeakidneystoneformer,withoutknowingit.Antioxidantscouldinterferewiththewaythebodyusesreactiveoxygenspeciesinfightingacutebacterialinfections.Also,someanticancerdrugsdependonreactiveoxygenspeciesfortheireffectiveness.Thus,duringthecourseofanacutebacterialinfectionorduringcancerchemotherapy,antioxidantsshouldbetakenonlyuponmedicaladvice.Finally,apersoniswell-advisedtotakeasupplementprogramdesignedforhisorherownparticularneeds;andonlyadoctorcandeterminewhattheseparticularneedsare.TheAllianceforAgingResearchrecommendationsfordailyintakelevelsarevitaminC,250-1,000mg;vitaminE,100-400mg;andbeta-carotene,10-30mg.Theyalsorecommendthataphysicianalwaysbeconsultedtosupervisethisprogram.
Ithasbeenclaimedthatbenefitsfromaddingtracemineralstotheregimenarelikelytobeminimalasthesewillsimplynotbeabsorbed,exceptincaseswherethepatient'sdietissopoorastobeshortofessentialminerals.However,aswehaveseen,calciumandmagnesiumformveryinsolublesaltswithundesirablefattyacidsintheintestinesandtherebyhelppreventtheirabsorption,thusremovingoneoftheriskfactorsforcolorectalcancer.Peopleatriskfor
osteoporosishaveaspecialneedforanadequateintakeofcalcium.
Thefailureofthegeneralpopulationtofollowgoodnutritionaladviceisparalleledbytheinabilityorunwillingnessofthebulkofthepopulationtotakeenoughexercise,asmanysurveysshow,andbythefactthatmanypeoplestillsmoketobacco,thesinglebiggestprobleminpreventativemedicine.
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Mostparticipantsinthisdebateassesstheneedtogiveornottogiveantioxidantsupplementsfromtheviewpointofjustonedisease,whetherheartdisease,cancer,cataract,diabetes,andsoon.However,raisingantioxidantintakemayprotectagainstawiderangeofdiseases,whichincreasesthebenefitsideoftherisk-benefitratio.
Theoxidativedamagethateventuallyleadstochronicdiseaseshasacumulativeeffectovermanyyears.Itwouldbeinefficienttotrytocorrectthisbymeansofantioxidantinterventionatalatestageintheprocess.Theantioxidantsshouldbegivenbeforethedamageisdone,aswesawclearlyinthecaseoftypeIdiabetesandParkinson'sdisease.Thetroubleisthatitisdifficulttopredictwhoisgoingtogetaparticulardisease.Incertaindiseases,suchasatherosclerosisandtypeIdiabetes,therearehighriskfactorswecanmeasure.Butwhataboutthosediseases,suchasParkinson'sdisease,nosuchmeasuresyetexist?IfeveryoneovertheageoffortyweretochangetoaMediterranean-stylediet,orpartakeofanadequateantioxidantprogramaswellasthebestdiettheycouldmanage,itseemsverylikelythattheincidenceofmanychronicdiseaseswouldfall.Ofcourse,thiscannotbeabsolutelyguaranteed,butmedicinewouldbeinasorrystateifonlymathematicaldegreesofcertaintyweretobeaccepted.WilliamRaspberry,inacolumnintheWashingtonPost,haspredictedthat,inviewofthecurrentseriousfinancialcrisisfacedbyMedicare,itwillsoonbefiscallyessentialforpeopletoadoptabetterdietandhealthierlifestyle.
Differentlevelsofantioxidantsupplementationmaybeneededfordifferentpurposes.Forexample,PryorshowedthatlevelsofvitaminEwellbelowtheRDAlevelareenoughtoprotectagainstmyopathy(muscledamage)[167].Preventionofredbloodcellhemolysis(rupture)requirestheRDAlevel.InthesetwocasesgivingmorethantheRDAconveysnofurtherbenefit.Buttoimprovethefunctionoftheimmunesystem,muchhigherlevelsthantheRDAarerequiredfor
maximumbenefit.AsPryorconcludes,"wehavepassedawatershedwithregardtoourattitudetowardtheuseofmicronutrientsandtheantioxidantvitamins."Last,andmostimportant,thereareconsiderabledifferencesamongpeopleastotheirantioxidantstatusandrequirements.Therefore,suggestingonelevelofsupplementationforeverybodyisaninefficientwaytoproceed.RemembertheadvicegivenbyTengerdythat,forvitaminE,
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theoptimumdosedependsonmanyfactorsandmustbedeterminedforeachindividual[213].Thisappliestootherantioxidantsaswell.IagreewithSnodderly'ssuggestionthatonerationalthingtodoistoobtainacomprehensiveblood-levelsurveyofthemostimportantantioxidants[204].AgoodmethodofdoingthisiscalledaPantoxprofile,whichincludesalipidandiron-balanceprofile.Thistestdetermineswhichantioxidantsapersonistakingenoughoftomeethisorherneeds,andofwhichmoreorlessisneeded.
Itseemslikelythatwithinafewyearsaphysicianwillnosoonerneglecttocarryoutaplasmaantioxidantprofileinhispatientsasfailtodoabloodglucoseorbloodpressuremeasurement.IsuggestthatallpatientswithanyofthediseasesIhavelisted,inwhichoxidativestressplaysanimportantrole,askthatsuchaprofilebeperformedasanessentialpartoftheinvestigativeworkupoftheirillness.Apparentlyhealthypeople,too,needaregularmonitoringoftheirantioxidantprofileasameasurethatmaycontributetopreventingthedevelopmentofsuchdiseaseslaterinlife.Physicianstodayexpendanenormousamountoftimeandenergyinhelpingpatientsfightoffattacksbydeadlybacteriaandviruses.Itisnowtimetofocusmoreattentiononhelpingpeoplefightofftheattacksontheirbodiesbyreactiveoxygenspecies,whichhavethepotentialtobeequallydeadly.
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appendixThefollowingisalistoffruitsandvegetablesandotherfoodsthataregoodsourcesofantioxidants.Aplussigndenotesanespeciallygoodsource.
CAROTENES
BETA- apricots,beetgreens,cantaloupe,carrots,chicory,collard
BETA-CAROTENE
apricots,beetgreens,cantaloupe,carrots,chicory,collardgreens,fennel,kale,mustardgreens,parsley,peaches,pumpkin,redpepper,romainelettuce,spinach,sweetpotatoes,Swisschard,watercress,wintersquash
LUTEINAND kale(+),broccoli,spinach,wintersquash,Brussels
ZEAXANTHINsprouts,celery,dill,leaflettuce,leeks,mustardgreens,parsley,peas,scallions,summersquash
LYCOPENE tomatoes(+),apricots,guava,pinkgrapefruit,mango,oranges,peaches,papaya,watermelon
VITAMINC broccoli,Brusselssprouts,cauliflower,citrusfruits,greenpepper,kiwi,kohlrabi,papaya,peaches,redcabbage,redpepper,strawberries,potatoes,alfalfa,lettuce
VITAMINE wheatgerm,seeds,nuts,margarine,darkgreenleafyvegetables,avocado,peanuts,sweetpotatoes
LIPOICACID darkgreenleafyvegetables,especiallyspinachandbroccoli
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FLAVONOIDS apples,citrusfruits,flaxseed,licorice,lentils,onions,peanuts,rice,soybeans,manyherbs,blueberries,cranberries(+),blackandredcurrants,loganberries(butlowinstrawberriesandraspberries);chamomiletea,oliveoil,redwine,tea
POLYPHENOLS chocolate,coffee,grapes,nuts,oranges,strawberries,tea,turmeric,whitewine
OTHERANTIOXIDANTS
chives,garlic,shallots,Brusselssprouts,rosemary,yeast
Suggesteddailyamountsforeffectivesupplementsofantioxidantsandantioxidanthelpers:
CAROTENES
BETA-CAROTENE 10mg
LUTEINE 10mg
LYCOPENE 10mg
ZEAXANTHIN 10mg
VITAMINB3 (NICOTINAMIDE) 100mg
VITAMINC 500mg
VITAMINE(ALPHA-TOCOPHEROL) 400-800mg
GAMM A-TOCOPH EROL 1OOmg
VITAMINQ 300m
GLUTAMINE(GLUTATHIONEPRECURSOR) 500mg
MIXEDISOPRENOIDS 20mg
SELENIUM 50mg
SELENIUM 50mg
ZINC 25mg
Totheabove,itwouldbeprudenttoaddvitaminB6(200mg),B12(1mg),andfolicacid(2mg),asmoderndietsareoftenlowintheseparticularvitamins.
However,itmightbewisertohaveanantioxidantprofilemeasuredbydoctorand,followinghisorheradvice,toadjustantioxidantintakeinaccordancewiththeprofile.
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abbreviationsALS amytrophiclateralsclerosis
CARET Beta-CaroteneandRetinolEfficiencyTrial
CAT catalase,anantioxidantenzyme
CHAOS CambridgeHeartAntioxidantStudy
DNA deoxyribonucleicacid,thecarrierofgeneticinformation
G gram
GSHpx glutathioneperoxidase,anantioxidantenzyme
HDL high-densitylipoprotein
L liter
LDL low-densitylipoprotein
L-DOPA levo-dihydroxyphenylalanine
MDA malonyldialdehyde,amarkerforfatoxidation
mg milligram
NAC n-acetylcysteine,anantioxidantNF-kB atranscriptionfactor,proteinthatswitchescertaingeneson
andoff
NHANES-I
FirstNationalHealthandNutritionExaminationSurvey
PGH prostaglandinH
PH Physician'sHealth
RDA recommendeddailyallowance
RDA recommendeddailyallowance
RNA ribonucleicacid
SOD superoxidedismutase,anantioxidantenzyme
TGFa ameasureofinflammation
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Page127
index
A
N-acetylcysteine(NAC),10
inacuteinfection,80
forAIDSpatients,74,75
andARDS,70,71
andEKGchanges,34
inneonate,83
inpancreatitis,83
insepticshockpatients,76
acuterespiratorydistresssyndrome(ARDS),antioxidantsfor,70-71,96
adrenalgland,andaging,73
adrenochrome,62
AfricanAmericans,heartdiseasein,30
aging,dietand,72-73
AIDS
antioxidantsfor,96
andoxidativestress,74
Aillet,F.,74
albumin,10,11
alcohol,andoralcancer,51
AllianceforAgingResearch,106
allicin,14,88
andcancerresearch,87
sourcesof,104
alliin,14
alliumvegetables,87
aloe-emodin(aloe),13
alpha-carotene,andlungcancer,45,49
alpha-limonene,15
alphalipoicacid,forAIDSpatients,74
alpha-tocopherol,1o.SeealsovitaminE
alpha-tocopherol-beta-carotene(ATBC)study,33,42,44,90,97,98
alternativemedicine,4
Alzheimer'sdisease,8
andantioxidants,54-55,96
causesof,53-54
preventionof,54-55
AmericanCancerSociety,39
AmericanJournalofClinicalNutrition,92
AmericanJournalofEpidemiology,49
aminoacids,ingarlic,14
amytrophiclateralsclerosis(ALS),57-58,96
anemia,beta-thalassemia,80
ANICAprotocol,andbreastcancer,48
Page128
anserine,13
anticancercompounds
curcumin,15
isoprenoids,15-16
insoybeans,13
intea,14
anti-inflammatoryagents,and
Alzheimer'sdisease,54
antioxidants.Seealsospecificantioxidantsandacuteinfections,79-80
balancedformulafor,42,43-44,49
andcancerdevelopment,46
deficiencyof,9
effectonarteriesof,35-36
essential,10
functionsof,3,9
helper,38
large-moleculeprotein,11
misleadinginformationon,96
needfor,96,105
plantsourcesof,12-15
potentialdangerof,80
preventativenatureof,20
propertiesof,9
protectiveeffectof,31
RDAsfor,96
reactiveoxygenspeciesand,17
safetyof,89-95
scienceof,2
sideeffectsof,1-2
small-molecule,10-11
synergismbetween,12,102
synthetic,66
antioxidantsupplements
andagingprocess,73
balancedregimenof,106
incancerprevention,39
andcarcinogenesis,51
fordiabetics,66
reasonsfor,107
antioxidanttherapy
complexitiesof,98
inprediabeticstage,65
antitumorcompounds,inrosemary,13.Seealsoanticancercompounds
apigenin,13,15
apples,36
protectiveeffectof,50
andquercetin,13
arachidonicacid,indiabetes,66
L-arginine,65
arthritis,prostaglandinsand,7
ascorbicacid(ascorbate),1o.SeealsovitaminC
aspirin
andPGHsynthase,8
andvitaminEtherapy,32
asthma,8,69-70,96
atheromatousplaque,23
atherosclerosis,8,72,87
antioxidantsupplementsfor,97
indialysispatients,84
earlyinterventionfor,107
preventionof,99
autoimmunediseases
diabetes,63-66
rheumatoidarthritis,84-85
ayurvedicmedicine,15
B
bacteria,andantioxidants,78
Barber,D.A.,100
Barton,J.C.,92
Bendich,A.,93
benzothiazines,61
beri-beri,2
berries,13
Bertoli,L.F,92
beta-amyloid,53
beta-blockers,andasthma,70
beta-carotene,1.Seealsocarotenes,2
andaging,73
inAIDSpatients,75
inAlzheimer'sdisease,53
inbeta-thalassemia,80
bloodlevelsof,22
andbreastcancer,47,48
andcancerrisk,40,41,42,43,98
andcataractformation,67
incigarettesmoking,71
incysticfibrosis,78
andfatoxidation,35
andheartattacks,34
andheartdisease,26,27,28,29
andhighbloodpressure,38
inHIVpatients,75
lowlevelsof,32
andlungcancer,45
ODCactivityreducedby,47
andoralcancer,51
Page129
inpancreatitis,83
protectiveeffectof,31,32,45,46
recommendationsfor,99,100,106
andriskforrheumatoidarthritis,85
roleof,11
safetyof,90
andsmokers,44
sourcesof,103,109
suggestedamountsfor,110
toxiclevelsof,100
beta-cells,indiabetes,64,65
beta-cryptoxanthin
andbreastcancer,48
andlungcancer,45
beta-thalassemia,80
beta-tyrosol,inoliveoil,14
Bettger,W.J.,102
BHT(butylatedhydroxytoluene),indiabetes,66
bilirubin
asantioxidant,11
andexposuretosmog,72
Blackburn,G.L.,104
blacktea,14
bladder,cancerof,40,41
Block,G.,40,92,101
bloodpressure,effectofantioxidantson,29,37-38
Blot,William,98
Blumberg,J.,98
boldine,15
boweldisease,inflammatory,82
Bowman,B.,99
brain
aging,73
inAlzheimer'spatients,53
cerebralvasospasm,77
andoxidativestress,52
braindamage,andantioxidants,52
breastcancer,41
andantioxidants,47-48,51
andsoy,85-86
Brown,K.M.,71
brusselssprouts,11o
Bukin,Y.V.,46
burns,prostaglandinsand,7
Bussey,H.J.R.,93
butter,antioxidantsfor,7
Byers,T.,99
C
caffeicacid,inoliveoil,14
calcium
andfattyacids,96
needfor,106
calories
reductionin,104
restrictionof,72
Cals,M.J.,73
Cameron,92
cancer
andantioxidants,39,40,98
breast,47-48,51,85-86
clinicalstudies,40-46
colorectal,50
lung,48-50,51
oral,51
prostate,51
roleofdietin,40
stomach,46-47,51
uterine,50-51
andvitaminC,92,93-94
canthaxanthin,90
cardiologists,antioxidantsupplementstakenby,102
CARETstudy(beta-caroteneandRetinolEfficacyTrial),41,44,90
carnosine,andglutamatesynapse,60
carotenes,10.Seealsospecificcarotenes
andbreastcancer,47-48
andcataractformation,68
andlungcancer,49
occurrenceof,11
protectiveeffectof,46
sourcesof,103,109
CarotenoidResearchInteractiveGroup,44
carotenoids
inAIDSpatients,74
andbeta-caroteneintake,90
andcancerrisk,98
andheartdisease,28
andlungcancer,49
andoralcancer,51
protectiveeffectof,31,32
andvitaminE,12
carotidarteries,andvitamintherapy,35
carrots,andcataracts,67
carvacuol,13
Page130
carvone,15
catalase(CAT),11,52,53
andaging,73
incancercells,39
incigarettesmoking,71
duringheartattack,25
inoxidativestress,22
inrenaldialysis,84
cataracts
andantioxidants,66-68
typesof,68
andvitaminC,93
catechins
inredwine,36
intea,13,14
cauliflower,andcancerrisk,49
Cecil'sTextBookofMedicine,98
cells
chemicalreactionsin,5
compositionof,6
energyproductionof,7
membraneof,6-7
cerebralvasospasm,77
cerebrospinalfluid,vitaminCin,84
cervix,cancerof,41,51
Chalmers,A.H.,90
Chamiec,T.,34
chamomiletea,13
Chandrasekar,B.,24
CHAOS(CambridgeHeartAntioxidantStudy),32,33
Chase,H.P.,64
chemotherapy,antioxidantsduring,1o6
China
folkmedicineof,82
Linxiantrialin,97
chives,11o
chlorpromazine,63
chocolate,13
cholesterol,LDL,23-24
andalcoholconsumption,86
andexercise,81
chorea,ofHuntington'sdisease,58
Christen,W.G.Jr,68
chronicobstructivepulmonarydisease(COPD),72
chrysin,15
citrusoils,15
claudication,intermittent,77
clinicaltrials,3-4,101.Seealsostudies
clotformation,24
clozapine,58
coffee,13
cold,common,79
collardgreens,andmaculardegeneration,68
coloncancer
anddiet,40
andsoy,85-86
colorectalcancer,50
Comstock,G.W.,45
ConsumerReports,2
copper
indiabetes,64
andvitaminC,100
coronaryarterydisease
causeof,23-24
studiesof,25-38
CoronaryPrimaryPreventionTrial,ofLipidResearchClinics,28
Coyle,J.T,8
Crohn'sdisease,82
cryptoxanthin,13
curcumin,15
5-cysteinyldopamine,61
cysticfibrosis
antioxidantsfor,96
causeof,77-78
cytokines,13
inAIDSpatients,74
duringheartattack,24
D
Daily,J.W.,92
deficiencydiseases,2,3,10
dementia,ofHuntington'sdisease,58
deRijk,M.C.,57
DeRijka,Y.B.,86
developingcountries,dietsin,104
diabetes
andantioxidants,64,96
causeof,63
earlyinterventionfor,107
increasein,105
treatmentof,56
type1,63-64
andvitaminC,93
dialysis,renal
andantioxidantintake,35
oxidativestressduring,84
Page131
dienes,conjugated,22
dieseloilfumes,8
diet
andcarcinogenesis,51
Mediterranean,29
needforbetter,4,104,107
protectiveeffectof,43
recommendationforprudent,100
ofU.S.population,95
vegetarian,50
Western,104
duringWorldWarII,105
dietaryfiber,incolorectalcancer,51
digestivetract,cancerof,41
Diplock,A.T.,41,44,5,68,9,98
disease,effectsofantioxidantsin,18-21
DNA
damageto,7,8
inHuntington'sdisease,58
oxidativeattackon,22
dopamine,55,56
andglutamatesynapse,60-61
quinonesderivedfrom,62
dopaminochrome,55,6
dose/responserelationship,40
double-blindstudies,19-20.Seealsostudies
Down'ssyndrome,53
Draper,H.H.,102
Dröge,W.,75
drugindustry,syntheticantioxidantsproducedby,12
E
eatinghabits,public'sneedtochange,104
Eaton,J.W.,77
Ebselen,76
EKGchanges,andvitamintherapy,34
electrons,transferof,5
emphysema,pulmonary,72
endive,andcancerrisk,49
enrichment,possibilitiesfor,102
Enstrom,J.E.,30
enzymes
antioxidant,9,22,39,52,53,57
essential,11
inrenaldialysis,84
epidemiologicalstudies,18,87,98
ofAlzheimer'sdisease,54
andbreastcancer,48
ofcataracts,66-68
ofeffectofsoy,85-86
NHANES1,49
ofteaconsumption,87
epigallocatechingallate,14
epinephrine,62
esophagus,cancerof,40
EstablishedPopulationforEpidemiologicalStudiesintheElderly,33
estrogens,anduterinecancer,50
EUK-8,70
Everall,I.P.,75
exerciseandantioxidants,81failureto,1o6
experiments,scientific,3-4.Seealsostudies
eyedisease,andantioxidants,66-69,100
F
fatintake
andantioxidantstatus,66
reductionin,104
fatoxidation
inAIDSpatients,74
inAlzheimer'sdisease,54
andbeta-carotene,44
indiabetics,64
anddiseaseprocess,7,8
effectofoliveoilon,14
effectofteaon,14
inheartdisease,23-24
inhyperthyroidism,81
measuringlevelsof,31
insepticshockpatients,76
andvitaminC,92
ferulicacid,inherbs,13
fiber,andbreastcancer,48
Finland
flavonoidstudyin,36
heartdiseasestudiesin,28-29,30
Finns.SeealsoLapps
cancerriskin,49-50
incancerriskstudy,42-43
vitaminCdeficiencyin,31
fisetin,13
Flagg,E.W.,40
flavins,intea,14
Page132
flavonoids,1
actionof,12-13
antioxidant,13
clinicaldataon,85-88
aspainrelievers,15
andParkinson'sdisease,57
protectiveeffectof,36,50
sourcesof,104,110
asvitaminEhelpers,13
Floren,L.C.,102
''foamycells,"24
folkmedicine,14
Chilean,15
Chinese,82
ofIndia,15
FoodandDrugAdministration(FDA),105
FoodandNutritionBoard,ofNAS,105
Franke,A.A.,51
freeradicals,6
"Frenchparadox,"36-37
Freudenheim.J.L.,47
fruits,12,13,102
anticancereffectsof,16,41
andbreastcancer,48
andcancerrisk,40,98
andcarcinogenesis,51
indiet,39,95
andlungcancer,48-49
protectiveeffectsof,43,103
G
Galley,H.F,38
gallicacid,innutgall,13
gamma-lineolicacid,andbreastcancer,48
gamma-tocopherol,10
andheartdisease,29,30
lowlevelsof,32
suggestedamountsfor,110
Garewal,H.S.,51,97
garlic,12,104,110asantioxidant,14clinicaldataon,87-88
gastriccancer,andvitaminE,45
Gehrig,Lou,58
gender,andeffectofantioxidants,31
Geniforte,15
genistin,13,85
geraniol,15
Gershoff,S.N.,68
Gey,K.F.,28,99,1oo
glucose-6-phosphatedehydrogenasedeficiency,93
glutamate,59
glutamine
forAIDSpatients,74
suggestedamountsfor,110
glutathione,56
inAIDSpatients,74
andasthma,69
incigarettesmoking,71
indiabetes,64,66
andgastriccarcinoma,45
inneonate,83
occurrenceof,10
potentialtoxicityof,77
inschizophrenia,62
andstrenuousexercise,81
inyeast,15
glutathioneperoxidase(GSHpx),111,52,53
inAIDSpatients,74
andasthma,69
incancercells,39
indiabetes,64
duringheartattack,25
inmaculardegeneration,69
inoxidativestress,22
inpreeclampsia,84
inrenaldialysis,84
inschizophrenia,62
Goldberg,D.M.,86
Goldfarb,S.,91
gossypol,13,15
grains,protectiveeffectof,43
grapefruit,13
greentea,13,14
Gridley,G.,51
H
H290/51,76
Halliwell,B.,46,103
haloperidol,63
Hankinson,S.E.,67
Harris,S.R.,1oo
Hathcock,J.N.,100
Hawking,Stephen,57
health-foodstores,1
healthinsuranceindustry,4
healthy-lifestylehypothesis,97
Page133
heartattack,90.Seealsomyocardialinfarction
andantioxidants,34
andfatoxidation,76-77
oxidativestressof,24
preventionof,25
andteaconsumption,87
heartdisease
andantioxidants,97,98
andoxidativestress,23-38
Helicobacterpylori,87
Hemil,H.,79
hemorrhagicstroke,55
Herbert,V.,30,92
herbs,12,13
Herman,Z.S.,79
Hertog,M.G.L.,36
hesperetin,inoranges,13
HIVinfection,8
andantioxidants,74-75
monocyteblockadein,75
Hodis,H.N.,35
Hoffer,Abram,4,61,62,63
Hoffman,R.M.,97
Hollman,P.C.H.,36
Huntington'sdisease,58
Huttunen,J.,97
hydrogenperoxide(H2O2),6
andasthma,70
andcancercells,39
inDown'ssyndrome,53
andglutamatesynapse,60
inParkinson'sdisease,56
inschizophrenia,59
hydroxylradical(OH)
asoxidatingagent,6
inpsychologicalstress,63
hydroxytyrosol,inoliveoil,13,14
hyperthyroidism,81
I
Illingworth,D.R.,97
immuneresponse
andaging,73
andvitaminC,79
andvitaminE,10,99-100
infections
andantioxidants,79-80
prostaglandinsand,7
inflammation
effectofflavonoidson,13
effectofoliveoilon,14
prostaglandinsand,7
andredwine,13
IowaHealthStudy,86
iron,free
incysticfibrosis,78
indiabetes,64
inrheumatoidarthritis,84
andvitaminC,91-92
ironoverload,andvitaminC,92-93
ischemia
antioxidantsfor,96
andoxidativestress,76
insystemicsclerosis,85
isoniazid,85
isoprenoids
indirectantioxidantpropertiesof,16
sourcesof,15-16
suggestedamountsfor,110
Italy,heartdiseasestudiesin,28
J
Jacques,P.F,67,94
Japanese,lungcancerratesin,87
JapaneseHawaiians,cancerriskin,45
Johnson,L.E.,100
JournaloftheAmericanCollegeofNutrition,98
K
kaempferol,14
kale,andmaculardegeneration,68
kidneystones,andvitaminC,9o-91
Kimmick,G.C.,47
Knekt,P.,45,49
kojo-kon,14
Krikker,M.,92
Kristensen,M.,29
Kuklinski,B,35
Kumar,R.,94
L
laboratorytests,effectofvitaminCon,93
Landrum,J.T.,69
Langseth,L.,93
Lapps,dietof,33
laryngealcancer
anddiet,40
roleofcarotenoidsin,5
LDLcholesterol,12
L-DOPA,56
learning,andantioxidants,60
Page134
Leewenburgh,C.,73
Lehr,H.-A.,72,76
lettuce,andcancerrisk,49
Levine,M.,100
licorice,13
Lih-Brody,L.,82
Linxiantrial,97
lipidperoxides,22
LipidResearchClinics,28
lipoicacid,10,11indiabeticpatients,65sourcesof,109
Lithuanians,heartdiseasein,29-30
Liu,Jiankang,60
liver,cirrhosisof
andantioxidants,80-81
indiabetes,65
Livrea,M.A.,80
Lockwood,K.,48
LouGehrig'sdisease,57-58,96
lungcancer
andantioxidants,41,48-50,51
anddiet,40
lutein,11
andbeta-caroteneintake,90
andbreastcancer,47-48
andlungcancer,49
andmaculardegeneration,68-69
sourcesof,103,109
suggestedamountsfor,110
lycopene,1,11,29
inbeta-thalassemia,80
andbreastcancer,48
andheartdisease,29
lowlevelsof,32
andlungcancer,45
inmaculardegeneration,69
andprostatecancer,41
protectiveeffectof,37,45
sourcesof,104,109
suggestedamountsfor,110
Lykkesfeldt,J.,71
lymphaticsystem,cancersof,40
M
macrophages,24
maculardegeneration
andantioxidants,68-69
andbeta-caroteneintake,90
magnesium
andfattyacids,96
needfor,106
malaria,82
Maloley,P.A.,97
MarioNegriInstitute,40
Marmite,15
Mason,Joel,98
massmedia,confusingreportsin,1-2
Matricariarecutitis,15
Maxwell,S.R.J.,97
MayoClinicgroup,92
McGeer,P.L.,54
McKeowen-Eyssen,G.,93
MDA(malonyldialdehyde),22
medicalcare,costsof,4
Medicare,4,107
Mediterraneandiet,29
megavitamins
vs.RDAs,2
suspicionof,17
Mehra,M.R.,99
melanoma,97
melatonin,1,11
Mena,M.A.,56
menopause,andheartdisease,27
menthol,15
Messmer,K.,76
Meyers,D.G.,97
micronutrients,107
mifepristone,12
minerals,96
mineralsupplements,18
mitochondrialdiseases,83
Moertel,C.G.,92
MONICA,28
monocytes,inHIVinfection,74
monosodiumglutamate,59
Mori,Akitane,60
morin,13
motorneurondisease,57-58
mouth,cancerof,40
multiplemyeloma,54
mutations,7
myocardialinfarction.Seealsoheartattack
antioxidantsfor,96
andvitaminQ10,35
andvitamintherapy,34
myo-inositol,indiabetes,66
myotonicdystrophy,83
myrecetin,14
N
NAC.SeeN-acetylcysteinenaringenin,ingrapefruit,13
Page135
nasopharyngealcancer,andteaconsumption,86
NationalAcademyofSciences(NAS)FoodandNutritionBoardof,105RDAspublishedby,2
NationalCancerInstitute,44,48,104
NationalHealthandNutritionExaminationSurveyI(NHANES-I),30,49
NationalResearchCouncil,105
nervoussystem,diseasesof,52-63
NetherlandsCohortStudyonDietandCancer,36,49
neuraltubedefects,indiabetes,66
neuroblastoma,vitaminCin,93
neuromelanin
inParkinson'sdisease,55
inschizophrenia,61
neurotransmitters,52
epinephrine,62
inschizophrenia,59
NewEnglandJournalofMedicine,41,43,54
NF-kBmolecule,8,22
nicotinamide(vitaminB3),12.SeealsovitaminB3
indiabetes,64-65
efficacyincombinationof,28
nitricoxide,61
andglutamatesynapse,60
andhighbloodpressure,38
nitricoxidesynthase,60
nitrogendioxide(NO2),72
nitrogenspecies,reactive,61
nitroglycerine,toleranceto,37
nitrosamines,effectofvitaminCon,46
NMDAreceptor,59,60
norepinephrine,62
Nurse'sHealthStudy,26
nutgall,13
nutrition
centersfor,1
guidelinesfor,104
physicians'attitudestoward,105
nuts,13
Nyyssönen,K.,30
O
obesity
andantioxidants,29
increasein,105
ODC(ornithinedecarboxylase),47
8-OH¬G,22,71
oleuropein,14
oliveoil,12,13,29
asantioxidant,14-15
protectiveeffectof,88
Oliver,M.F,97
Omage,S.T.,44
Omenn,G.S.,44,98
onions
flavonoidsin,36
protectiveeffectof,50,87
oralcancer
preventionof,51
andteaconsumption,86
oranges,13
organmeats,vitaminQ10in,11
Osmond,Humphry,4,61,62,63
osteoporosis,calciumfor,106
ovary,cancerof,41
oxalicacid,90-91
oxidants,3
oxidation,5
oxidativestress,3,5
inAIDSpatients,74
inAlzheimer'sdisease,53,55
andbloodflowinterruption,76
causesof,8-9
andcellularmetabolism,22
incigarettesmoking,71,72
indiabetes,64
indisease,22-23
andheartdisease,23-38
inhyperthyroidism,81
andincreasedfoodconsumption,72
inlungs,69
inmalaria,82
measurementof,21-22
neonatal,83
Pantoxprofilefor,108
andParkinson'sdisease,56
inpreeclampsia,84
reperfusion,76-77
inshockpatients,76
andstroke,52
oxidizingagents,6
oxygenspecies,reactive,6,17,46
inAlzheimer'sdisease,54
body'sdefensesagainst,95
andbraincells,8
andcaloricrestriction,73
cancer-producing,39
Page136
oxygenspecies,reactive(cont'd)
incigarettesmoking,71
indiabetes,64
fighting,108
duringheartattack,25
inHuntington'sdisease,58
productionof,9
proteinattackedby,7
inschizophrenia,59
andWBCs,7
P
Packer,L.,44,65
painrelievers,flavonoidsas,15
Paller,M.S.,77
pancreas
cancerof,40,41
failureof,78
pancreatitis,83
Panetta,J.A.,85
Pantoxprofile,108
Paolisso,G.,93
parasiticfoci,inschizophrenia,59
Parkinson'sdisease,20-21
antioxidantsfor,56-57,96
causesof,55-56
earlyinterventionfor,107
symptomsof,56
treatmentof,56
passifloracoerulea,15
Patterson,B.H.,104
Pauling,Linus,2-3,79,90,92
Paulson,G.W.,57
peanuts
lycopenein,103
reservatolin,13
pellagra,2,10
pentane,22
peptides,antioxidant,13
peroxynitrite,61
PGHsynthase,7
pharyngealcancer,andteaconsumption,86
phenols
antioxidant,13
andflavonoids,12
physicians
andantioxidanttherapy,108
dietaryadviceof,105
Physician'sHealthStudy,27,42
phytochemicals,12
placebo
inantioxidantstudies,19-20
indouble-blindstudies,32-34
plants,antioxidantsfoundin,12-15
plasmaantioxidantprofile,108
platelets
effectofflavonoidson,13
effectofoliveoilon,14
effectofvitaminEon,24
andredwine,13
pneumococcalmeningitis,80
polygonumcuspidatum,14
polyphenols,50
antioxidant,13
sourcesof,104,110
portwine,14
potatoes,vitaminCin,97
Prasad,K.N.,94
preeclampsia,84
probucol,64
procysteine,andARDSpatients,71
progesterone,11
pro-oxidants,6
propaganda,4
prospectivestudies,98
prostaglandinHsynthase(PGHsynthase)
inAlzheimer'sdisease,53
ininflammationprocess,7
inschizophrenia,59
prostaglandins
effectofflavonoidson,13
effectofredwineon,13
duringinflammation,7
prostatecancer
andantioxidants,41,51
andsoy,85-86
proteins
andreactiveoxygenspecies,7
roleof,7
sacrificial,10
proteins,blood,andsmogexposure,72
Pryor,W.A.,107
pseudomonasaeruginosa,78
PSstudy,44
psychologicalstress,63
Q
qinghaosu,82
quercetin,14,15
inapples,13
Page137
protectiveeffectof,50
inredwine,36
quinones,61
derivedfromdopamine,62
inschizophrenia,61
R
Rachmilewitz,E.A.,81
Ramsey,B.W.,78
Raspberry,William,107
Rautalahti,M.,97
Raynaud'ssyndrome,81
recommendeddailyallowances(RDAs),2
ofantioxidantvitamins,105
raising,106
replacementof,99
rectum,cancerof,40
redwineclinicaldataon,86flavonoidsin,13protectiveeffectof,36-37
Reider,C.R.,57
reinforcement,positive,andantioxidants,60
reperfusion
antioxidantsfor,96
andoxidativestress,76
insystemicsclerosis,85
reservatol,11
actionof,13-14
inredwine,36
respiratorydiseases,andantioxidants,69-72
respiratorytract,cancerof,41
rhein,inrhubarb,13
rheumatoidarthritis,8,84-85
rhubarb,13
riboflavin,andcataracts,67
rice,13
Riemersma,R.A.,28
Rimm,E.B.,26
rosemary,13,110
Rucker,R.B.,17
rutin,inredwine,13,36
S
Santini,S.A.,64
Scheider,W.L.,57
schizophrenia
antioxidantdefensesin,62
antioxidantsin,61,96
causesof,59-61
norepinephrinepathwayin,62
oxidativestressin,4
typesof,58-59
Schmidt,K.-H.,91
scleroderma,85
Scotland,heartdiseasestudiesin,28
ScottishHeartHealthStudy,27
scurvy,2,10
seeds,13
selegiline,andAlzheimer'sdisease,54-55
selenium,96
inAIDSpatients,74
andARDS,70
andasthma,69-70
andbreastcancer,48
indiabeticpatients,65
andfatoxidation,35
inHIVpatients,75
recommendationsfor,100
andriskforrheumatoidarthritis,85
insepticshockpatients,76
suggestedamountsfor,110
toxiclevelsof,100
asvitaminEhelper,103
self-medication,97
Sen,C.K.,81
SeventhDayAdventists,heartdiseasein,30
shallots,104,1
shock
andantioxidantdefenses,75-76
antioxidantsfor,96
silymarin,indiabeticpatients,60
Simonian,N.A.,8
Singh,R.B.,29,34
smog,exposureto,72
smoking,90,106
andantioxidants,37,71-72
andbeta-carotene,26,42,44
andcarotenoids,28
andlungcancer,49
Snodderly,D.M.,1o8
soy
anticancercompoundsin,13
clinicaldataon,85-86
spinach
andcataracts,67
andmaculardegeneration,68
Page138
Sthelin,H.B.,45
Stampfer,M.J.,26
Stephens,N.G.,32,33
steroids,12
Stites,T,17
stomachcancer
andantioxidants,41,46-47,51
anddiet,40
stress
vs.oxidativestress,23
psychological,63
stroke,andantioxidants,52
studies.Seealsoepidemiologicalstudies;specificstudies
coronaryarterydisease,25-38
double-blind,placebo-controlled,18,19-20,32-34,41,43,47,55,65,70,75,98,99,101
limitationsof,20-21
randomized,double-blindIcontrolled,34
sunflowerseedoil,36
superoxidedismutase(SOD),11,53,57,58
duringheartattack,25
inmaculardegeneration,69
inoxidativestress,22
potentialtoxicityof,77
inrenaldialysis,84
superoxideion(0-),6
supplementation,suspicionof,17
SurgeonGeneral,105
Swedishmen,heartdiseasein,29-30
synapsedeletion,inschizophrenia,59
syntheticmolecules,12
systemicsclerosis,85
T
Tavani,A.,40
Taylor,A.,68
tea,12,13,36
asantioxidant,14
clinicaldataon,86-87
television,advertisingon,105
Tengerdy,R.P.,99,107
4-thiazolidinone,85
thrombolytictreatment,antioxidantsin,77
thromboxanes,effectofoliveoilon,14
thyme,13
thymol,13
Timemagazine,1-2
tobacco,andoralcancer,51
tobaccosmoke,8
Tolbert,Leland,3
tomatoes,29,103
andmaculardegeneration,69
protectiveeffectof,37
Toohey,L.,30
traceminerals,1o6
transmethylation,61
transmethylationhypothesis,4
transplantsurgery,oxidativestressof,76
Trichopoulou,A.,88
tuberculosis,andantioxidantdefenses,85
tumeric,15
turniptops,andmaculardegeneration,68
U
ulcerativecolitis,82
ulcers
antioxidantsfor,63
andgarlicconsumption,87-88
"uncontrolledvariable"problem,19
urate,andgastriccarcinoma,45
uricacid,11,14indiabetes,64inpreeclampsia,84
Urivetsky,M.,91
uterinecancer,andantioxidants,50-51
V
Valium,15
VanderHagen,A.M.,1oo
VanderVliet,A.,78
vanillicacid,inoliveoil,14
LaVecchia,C.,40
vegetables,12,102
allium,87
anticancerpropertiesof,16,41
andbreastcancer,48
andcancerrisk,40,98
andcarcinogenesis,51-52
indiet,39,95
andlungcancer,48-49
protectiveeffectsof,43,103
vegetariandiet,50
vitaminA,1,10
inAIDSpatients,75
inbeta-thalassemia,80
andcancerrisk,41
indiabetes,64
Page139
vitaminB3.Seealsonicotinamide
suggestedamountsfor,110
asvitaminEhelper,102,103
vitaminB6
inAIDSpatients,75
suggestedamountsfor,110
vitaminB12
inAIDSpatients,75
suggestedamountsfor,110
vitaminC,1,2
allegedtoxicityof,93
andcommoncold,79
antinitrosamineactionof,51
andARDS,70
andasthma,69,70
inbeta-thalassemia,80
bloodlevelsof,22
inbrain,52,56
andbreastcancer,47,48
afterbypasssurgery,35
cancerand,40
andcancerrisk,98
andcataracts,66,67-68
incigarettesmoking,71,72
incombinationdoses,94
incysticfibrosis,78
indiabetes,64,66
effectonnitrosaminesof,46
efficacyincombination,28
fat-solublederivativesof,12,21
andgastriccarcinoma,45
andglutamatesynapse,60
andheartdisease,26-27,28,29,30
andhighbloodpressure,38
inHIVpatients,75
andlipoicacid,11
lowlevelsof,32
andlungcancer,49
andnitrosamines,103
occurrenceof,10
andoralcancer,51
inpancreatitis,83
andParkinson'sdisease,57
pro-oxidanteffectof,93
protectiveeffect1f,31,32
RDAfor,2,100-101
recommendationsfor,97,99,100,106
safetyof,90-94
inschizophrenia,62
insepticshockpatients,76
andsmogexposure,72
sourcesof,104,109
andstrenuousexercise,81
suggestedamountsfor,110
insystemicsclerosis,85
toxiclevelsof,100
andvitaminE,12,32,102,103
vitaminCdeficiency,30-31,32
vitaminCsupplements,duringL-DOPAtherapy,56
vitaminD
anticancereffectof,42
forsmokers,42
vitaminE,1,2
inAIDSpatients,74,75
andALS,57-58
andAlzheimer'sdisease,54-55
andARDS,70
andasthma,69
inbeta-thalassemia,80
bloodlevelsof,22
andbreastcancer,47,48
afterbypasssurgery,35
andbypasssurgery,77
andcancerrisk,40,42,43,45,98
andcataracts,66,67,68
incigarettesmoking,71,72
incysticfibrosis,78
indiabetes,64,65,66
effectonplateletsof,24
efficacyincombinationof,28
andfatoxidation,35
andgastriccarcinoma,45
andheartattacks,33,34
andheartdisease,26-27,29
helpervitaminsfor,102
andhighbloodpressure,38
inhyperthyroidism,81
andimmuneresponse,73
andlipoicacid,11
lowlevelsof,32
andlungcancer,49
moppingupoperationof,94
andnitroglycerinetherapy,37
ODCactivityreducedby,47
optimumdosefor,107-108
andoralcancer,51
inpancreatitis,83
andParkinson'sdisease,57
protectiveeffectof,31,32,38,46
RDAfor,2,38
Page140
vitaminE(cont'd)
recommendationsfor,97,99,100,106
andriskforrheumatoidarthritis,85
roleof,10
safetyof,94-95
insepticshockpatients,76
andsmogexposure,7
sourcesof,104,109
andstrenuousexercise,81
suggestedamountsfor,110
insystemicsclerosis,85
toxiclevelsof,100
vitaminEsupplements,103
vitaminK,55
vitaminQ10,10
andbreastcancer,48
andhighbloodpressure,38
protectiveeffectof,35-36
andsmogexposure,72
suggestedamountsfor,110
inyeast,15
vitamins
industryfor,1
typesof,10-11
vitaminsupplements,18
andcataracts,67-68
self-medicationwith,97
Voelker,R.,18
W
Wales,coronaryheartdiseasestudyin,87
Walker,A.R.P.,104
water(H20),6
Weber,P.,103
Weinsier,Roland,98
Weisburger,J.H.,99,100
whitebloodcells,7
whitewine,13.Seealsoredwine,36
wholegraincereals,13
Winklhofer-Roob,B.M.,78
Wiseman,H.,103
Wiseman,Helen,46
WorkStudyGrouponDiet,NutritionandCancer,ofACS,39
WorldHealthOrganization,MONICAprojectof,28
Y
yeast,15,110
Yong,L.-C.,49
Z
Z-103,76
zeaxanthin,1,11
andbeta-caroteneintake,90
andbreastcancer,48
andlungcancer,49
andmaculardegeneration,68-69
sourcesof,103,109
suggestedamountsfor,110
Zemel,M.B.,92
Ziegler,R.G.,45,48
zinc,100
inAIDSpatients,74
andhighbloodpressure,38
suggestedamountsfor,110