review article chemistry and biological activities of ...1. introductionflavonoids consist of a...

Hindawi Publishing CorporationThe Scientific World JournalVolume 2013 Article ID 162750 16 pageshttpdxdoiorg1011552013162750

Review ArticleChemistry and Biological Activities of Flavonoids An Overview

Shashank Kumar and Abhay K Pandey

Department of Biochemistry University of Allahabad Allahabad 211002 India

Correspondence should be addressed to Abhay K Pandey akpandey23rediffmailcom

Received 24 August 2013 Accepted 7 October 2013

Academic Editors K P Lu and J Sastre

Copyright copy 2013 S Kumar and A K Pandey This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

There has been increasing interest in the research on flavonoids fromplant sources because of their versatile health benefits reportedin various epidemiological studies Since flavonoids are directly associated with human dietary ingredients and health there is needto evaluate structure and function relationship The bioavailability metabolism and biological activity of flavonoids depend uponthe configuration total number of hydroxyl groups and substitution of functional groups about their nuclear structure Fruits andvegetables are the main dietary sources of flavonoids for humans along with tea and wine Most recent researches have focusedon the health aspects of flavonoids for humans Many flavonoids are shown to have antioxidative activity free radical scavengingcapacity coronary heart disease prevention hepatoprotective anti-inflammatory and anticancer activities while some flavonoidsexhibit potential antiviral activities In plant systems flavonoids help in combating oxidative stress and act as growth regulatorsFor pharmaceutical purposes cost-effective bulk production of different types of flavonoids has been made possible with the helpof microbial biotechnology This review highlights the structural features of flavonoids their beneficial roles in human health andsignificance in plants as well as their microbial production

1 Introduction

Flavonoids consist of a large group of polyphenolic com-pounds having a benzo-120574-pyrone structure and are ubiq-uitously present in plants They are synthesized by phenyl-propanoid pathway Available reports tend to show that sec-ondary metabolites of phenolic nature including flavonoidsare responsible for the variety of pharmacological activities [12] Flavonoids are hydroxylated phenolic substances and areknown to be synthesized by plants in response to microbialinfection [3] Their activities are structure dependent Thechemical nature of flavonoids depends on their structuralclass degree of hydroxylation other substitutions and con-jugations and degree of polymerization [4] Recent interestin these substances has been stimulated by the potentialhealth benefits arising from the antioxidant activities of thesepolyphenolic compounds Functional hydroxyl groups inflavonoids mediate their antioxidant effects by scavengingfree radicals andor by chelating metal ions [5 6] Thechelation of metals could be crucial in the prevention ofradical generation which damage target biomolecules [7 8]

As a dietary component flavonoids are thought to havehealth-promoting properties due to their high antioxidantcapacity both in vivo and in vitro systems [9 10] Flavonoidshave ability to induce human protective enzyme systemsThe number of studies has suggested protective effectsof flavonoids against many infectious (bacterial and viraldiseases) and degenerative diseases such as cardiovasculardiseases cancers and other age-related diseases [2 8ndash10]Themechanisms involved in protection provided by flavonoidsare described separately in this review Flavonoids also actas a secondary antioxidant defense system in plant tissuesexposed to different abiotic and biotic stresses Flavonoids arelocated in the nucleus ofmesophyll cells andwithin centers ofROS generation They also regulate growth factors in plantssuch as auxin [11] Biosynthetic genes have been assembledin several bacteria and fungi for enhanced production offlavonoids [12] This review deals with the structural aspectsof flavonoids and their protective roles against many humandiseases Functions of flavonoids in plants and theirmicrobialproduction have also been described

2 The Scientific World Journal

A C

BO1

2

3

456

78 1

998400

2998400

3998400

4998400

5998400

6998400

Figure 1 Basic flavonoid structure

2 Chemistry of Flavonoids

Flavonoids are a group of natural compounds with variablephenolic structures and are found in plants In 1930 a newsubstance was isolated from oranges At that time it wasbelieved to be a member of a new class of vitamins and wasdesignated as vitamin P Later on it became clear that thissubstancewas a flavonoid (rutin) and till nowmore than 4000varieties of flavonoids have been identified [13]

Chemically flavonoids are based upon a fifteen-carbonskeleton consisting of two benzene rings (A and B asshown in Figure 1) linked via a heterocyclic pyrane ring(C) They can be divided into a variety of classes such asflavones (eg flavone apigenin and luteolin) flavonols (egquercetin kaempferol myricetin and fisetin) flavanones(eg flavanone hesperetin and naringenin) and othersTheir general structures are shown in Table 1 The variousclasses of flavonoids differ in the level of oxidation andpatternof substitution of the C ring while individual compoundswithin a class differ in the pattern of substitution of the A andB rings [13]

Flavonoids occur as aglycones glycosides and methy-lated derivatives The basic flavonoid structure is aglycone(Figure 1) Six-member ring condensed with the benzenering is either a 120572-pyrone (flavonols and flavanones) or itsdihydroderivative (flavonols and flavanones) The positionof the benzenoid substituent divides the flavonoid classinto flavonoids (2-position) and isoflavonoids (3-position)Flavonols differ from flavanones by hydroxyl group at the 3-position and a C2ndashC3 double bond [40] Flavonoids are oftenhydroxylated in positions 3 5 7 2 31015840 41015840 and 51015840 Methyl ethersand acetyl esters of the alcohol group are known to occur innature When glycosides are formed the glycosidic linkageis normally located in positions 3 or 7 and the carbohydratecan be L-rhamnose D-glucose glucorhamnose galactose orarabinose [41]

21 Spectral Characteristics of Flavonoids Studies onflavonoids by spectroscopy have revealed that most flavonesand flavonols exhibit two major absorption bands Band I(320ndash385 nm) represents the B ring absorption while BandII (250ndash285 nm) corresponds to the A ring absorptionFunctional groups attached to the flavonoid skeleton maycause a shift in absorption such as from 367 nm in kaempferol(35741015840-hydroxyl groups) to 371 nm in quercetin (3573101584041015840-hydroxyl groups) and to 374 nm in myricetin (357310158404101584051015840-hydroxyl groups) [42] The absence of a 3-hydroxyl group in

flavones distinguishes them from flavonols Flavanones havea saturated heterocyclic C ring with no conjugation betweenthe A and B rings as determined by their UV spectralcharacteristics [43] Flavanones exhibit a very strong BandII absorption maximum between 270 and 295 nm namely288 nm (naringenin) and 285 nm (taxifolin) and only ashoulder for Band I at 326 and 327 nm Band II appears asone peak (270 nm) in compounds with a monosubstituted Bring but as two peaks or one peak (258 nm) with a shoulder(272 nm) when a di- tri- or o-substituted B ring is presentAs anthocyanins show distinctive Band I peak in the 450ndash560 nm region due to hydroxyl cinnamoyl system of the Bring and Band II peaks in the 240ndash280 nm region due to thebenzoyl system of the A ring the colour of the anthocyaninsvaries with the number and position of the hydroxyl groups[44]

3 Flavonoid Rich Food and Medicinal Plants

Flavonoids are the most common and widely distributedgroup of plant phenolic compounds occurring virtually inall plant parts particularly the photosynthesising plant cellsThey are a major coloring component of flowering plantsFlavonoids are an integral part of human and animal dietSome food sources containing different classes of flavonoidsare given in Table 2 Being phytochemicals flavonoids cannotbe synthesized by humans and animals [45] Thus flavonoidsfound in animals are of plant origin rather than being biosyn-thesized in situ Flavonols are the most abundant flavonoidsin foods Flavonoids in food are generally responsible forcolour taste prevention of fat oxidation and protection ofvitamins and enzymes [46] Flavonoids found in the highestamounts in the human diet include the soy isoflavonesflavonols and the flavones Although most fruits and somelegumes contain catechins the levels vary from 45 to610mgkg [47] Preparation and processing of food maydecrease flavonoid levels depending on the methods usedFor example in a recent study orange juices were found tocontain 81ndash200mgL soluble flavanones while the contentin the cloud was 206ndash644mgL which suggest that theflavanones are concentrated in the cloud during processingand storage [48] Accurate estimation of the average dietaryintake of flavonoids is difficult because of thewide varieties ofavailable flavonoids and the extensive distribution in variousplants and also the diverse consumption in humans [49]

Recently there has been an upsurge of interest in thetherapeutic potential of medicinal plants which might bedue to their phenolic compounds specifically to flavonoids[50 51] Flavonoids have been consumed by humans sincethe advent of human life on earth that is for about 4million years They have extensive biological properties thatpromote human health and help reduce the risk of diseasesOxidative modification of LDL cholesterol is thought to playa key role during atherosclerosis The isoflavan glabridin amajor polyphenolic compound found in Glycyrrhiza glabra(Fabaceae) inhibits LDL oxidation via a mechanism involv-ing scavenging of free radicals [52] Several epidemiologicstudies have suggested that drinking either green or black

The Scientific World Journal 3

Table 1 Structure of flavonoids

Group offlavanoid Structure backbone Examples

FlavonesO

O

O

O

HO

OH

HOOH

Luteolin

O

O

HO

OH

OH

Apigenin

O

O

HO

OH

Chrysin

FlavonolsO

OOH

O

OOH

HO

OH

OHHO

Quercetin

O

OOH

HO

OH

OH

Kaempferol

O

OOH

HO

OH

Galangin

FlavanonesO

O

O

O

HO

OH

HOO

Hesperetin

CH 3 O

O

HO

OH

OH

Naringenin

FlavanonolO

OOH

O

OOH

HO

OH

OHOH

Taxifolin

Isoflavones

O

O

O

OOH

HO

OH

Genistein

O

OOH

HO

Daidzein

Flavan-3-olsO

OH

O

OH

HO

OH

OHOH

Catechin

O

OH

HO

OH

OH

OH

Epicatechin

tea may lower blood cholesterol concentrations and bloodpressure thereby providing some protection against cardio-vascular disease Flavonoids are also known to influencethe quality and stability of foods by acting as flavorantscolorants and antioxidants [53 54] Flavonoids containedin berries may have a positive effect against Parkinsonrsquosdisease and may help to improve memory in elderly peopleAntihypertensive effect has been observed in total flavonoidfraction of Astragalus complanatus in hypertensive rats [55]Intake of antioxidant flavonoids has been inversely related to

the risk of incidence of dementia [56] Table 3 summarizessome of the medicinal plants rich in flavonoid contents

Solubility may play major role in the therapeutic efficacyof flavonoids Low solubility of flavonoid aglycones in watercoupled with its short residence time in the intestine as wellas its lower absorption does not allow humans to suffer acutetoxic effects from the consumption of flavonoids with theexception of a rare occurrence of allergyThe low solubility ofthe flavonoids inwater often presents a problem for itsmedic-inal applications Hence the development of semisynthetic


Table 2 Classification structure and food sources of some dietary flavonoids

Class Flavonoid Dietary source References

Flavanol(+)-Catechin(minus)-EpicatechinEpigallocatechin

Tea [14]

FlavoneChrysin apigeninRutin luteolin andluteolin glucosides

Fruit skins red wine buckwheat red pepper and tomato skin [15ndash18]

Flavonol Kaempferol quercetinmyricetin and tamarixetin Onion red wine olive oil berries and grapefruit [17]

Flavanone Naringin naringenin taxifolinand hesperidin Citrus fruits grapefruits lemons and oranges [19 20]

Isoflavone Genistin daidzin Soyabean [21]Anthocyanidin Apigenidin cyanidin Cherry easberry and strawberry [17 18]

Table 3 Medicinal plants rich in flavonoids contents

Plant Family Flavonoid ReferencesAloe vera Asphodelaceae Luteolin [22]Acalypha indica Euphorbiaceae Kaempferol glycosides [22]Azadirachta indica Meliaceae Quercetin [23]Andrographis paniculata Acanthaceae 5-hydroxy-78-dimethoxyflavone [24]Bacopa moneirra Scrophulariaceae Luteolin [22]Betula pendula Betulaceae Quercetrin [24]Butea monospermea Fabaceae Genistein [25]Bauhinia monandra Fabaceae Quercetin-3-O-rutinoside [25]Brysonima crassa Malphigaceae (+)-catechin [26]Calendula officinalis Compositae isorhamnetin [24]Cannabis sativa Compositae Quercetin [24]Citrus medica Rutaceae hesperidin [22]Clerodendrum phlomidis Verbenaceae Pectolinarigenin [23]Clitoria ternatea Fabaceae kaempferol-3-neohesperidoside [27]Glyccheriza glabra Leguminosae Liquiritin [24]Mimosa pudica Mimosoideae Isoquercetin [28]Limnophila indica Scrophulariaceae 34-methlenedioxyflavone [28]Mentha longifolia Lamiaceae Luteolin-7-O-glycoside [29]Momordica charantia Curcurbitaceae Luteolin [30]Oroxylum indicum Bignoniaceaea Chrysin [28]Passiflora incarnate Passifloraceae Vitexin [24]Pongamia pinnata Fabaceae Pongaflavonol [31]Tephrosia purpurea Fabaceae Purpurin [28]Tilia cordata Tiliaceae hyperoside [24]

water-soluble flavonoids for example hydroxyethylrutosidesand inositol-2-phosphatequercetin has been implicated forthe treatment of hypertension and microbleeding [57]

4 Metabolism of Flavonoids in Humans

The absorption of the dietary flavonoids liberated fromthe food by chewing will depend on its physicochemicalproperties such asmolecular size configuration lipophilicitysolubility and pKa The flavonoid can be absorbed from thesmall intestine or has to go to the colon before absorption

It may depend upon structure of flavonoid that is whetherit is glycoside or aglycone Most flavonoids except for thesubclass of catechins are present in plants bound to sugarsas b-glycosides (Figure 2) Aglycans can be easily absorbedby the small intestine while flavonoid glycosides have to beconverted into aglycan form [58]

The hydrophilic flavonoid glucoside such as quercetinare transported across the small intestine by the intesti-nal Na+-dependent glucose cotransporter (SGLT1) [58]An alternative mechanism suggests that flavonoid gluco-sides are hydrolyzed by lactase phloridzin hydrolase (LPH)


O

O

OO

OH

OH

OH

OH

OH

OH

HO

HO

(a)

O

O

OH

OH

OH

OH

HO

(b)

Figure 2 Structure of (a) flavonoid glycoside and (b) aglycone flavonoid

a 120573-glucosidase on the outside of the brush bordermembraneof the small intestine Subsequently the liberated aglyconecan be absorbed across the small intestine [59] The sub-strate specificity of this LPH enzyme varies significantlyin a broad range of glycosides (glucosides galactosidesarabinosides xylosides and rhamnosides) of flavonoids [60]The glycosides which are not substrates for these enzymesare transported toward the colon where bacteria have abilityto hydrolyze flavonoid glycosides but simultaneously theywill also degrade the liberated flavonoid aglycones [61] Sinceabsorption capacity of the colon is far less than that of thesmall intestine only trivial absorption of these glycosides isto be expected

After absorption the flavonoids are conjugated in theliver by glucuronidation sulfation or methylation or metab-olized to smaller phenolic compounds [62] Due to theseconjugation reactions no free flavonoid aglycones can befound in plasma or urine except for catechins [63] Depend-ing on the food source bioavailability of certain flavonoidsdiffers markedly for example the absorption of quercetinfrom onions is fourfold greater than that from apple or tea[64] The flavonoids secreted with bile in intestine and thosethat cannot be absorbed from the small intestine are degradedin the colon by intestinal microflora which also break downthe flavonoid ring structure (Figure 3) Oligomeric flavonoidsmay be hydrolyzed to monomers and dimers under influenceof acidic conditions in the stomach Larger molecules reachthe colon where they are degraded by bacteria The sugarmoiety of flavonoid glycosides is an important determinantof their bioavailability Dimerization has been shown toreduce bioavailability Among all the subclasses of flavonoidsisoflavones exhibit the highest bioavailability [65] Afteringestion of green tea flavonoid content is absorbed rapidlyas shown by their elevated levels in plasma and urine Theyenter the systemic circulation soon after ingestion and causea significant increase in plasma antioxidant status [66]

5 Biological Activities of Flavonoids

51 Antioxidant Activity Flavonoids possessmany biochemi-cal properties but the best described property of almost every

Flavonoids(Ring form)

Colon

Small intestine

Feces

LiverOther tissue

Kidney

Urine

Flavonoids(Broken ring

form)

Figure 3 Compartments involved in the metabolism of flavonoid

group of flavonoids is their capacity to act as antioxidantsThe antioxidant activity of flavonoids depends upon thearrangement of functional groups about the nuclear struc-ture The configuration substitution and total number ofhydroxyl groups substantially influence several mechanismsof antioxidant activity such as radical scavenging and metalion chelation ability [4 67] The B ring hydroxyl configu-ration is the most significant determinant of scavenging ofROS and RNS because it donates hydrogen and an electronto hydroxyl peroxyl and peroxynitrite radicals stabilizingthem and giving rise to a relatively stable flavonoids radical[68]

Mechanisms of antioxidant action can include (1) sup-pression of ROS formation either by inhibition of enzymesor by chelating trace elements involved in free radical gener-ation (2) scavenging ROS and (3) upregulation or protectionof antioxidant defenses [69 70] Flavonoid action involvesmost of the mechanisms mentioned above Some of theeffects mediated by them may be the combined result ofradical scavenging activity and the interaction with enzymefunctions Flavonoids inhibit the enzymes involved in ROSgeneration that is microsomal monooxygenase glutathione


OH

OH

Fl-OH

R∘ RH

O∘

OH

∘F1-O

O∘

OH

R∘ RH OO

(a)

HO

A

O

O

Men+Men+

OH

B3998400

4998400

HO Men+

OH

(b)

Figure 4 (a) Scavenging of ROS (R∘) by flavonoids (Fl-OH) and (b) binding sites for trace metals where Me119899+ indicates metal ions

S-transferase mitochondrial succinoxidase NADH oxidaseand so forth [71]

Lipid peroxidation is a common consequence of oxidativestress Flavonoid protect lipids against oxidative damageby various mechanisms [5 51] Free metal ions enhanceROS formation by the reduction of hydrogen peroxide withgeneration of the highly reactive hydroxyl radical Due totheir lower redox potentials flavonoids (Fl-OH) are ther-modynamically able to reduce highly oxidizing free radicals(redox potentials in the range 213ndash10 V) such as superoxideperoxyl alkoxyl and hydroxyl radicals by hydrogen atomdonation (Figure 4(a)) Because of their capacity to chelatemetal ions (iron copper etc) flavonoids also inhibit freeradical generation [70 72] Quercetin in particular is knownfor its iron-chelating and iron-stabilizing properties Tracemetals bind at specific positions of different rings of flavonoidstructures [73] The binding sites are shown in Figure 4(b)

A 3101584041015840-catechol structure in the B ring firmly enhancesinhibition of lipid peroxidationThis trait of flavonoidsmakesthem most effective scavengers of peroxyl superoxide andperoxynitrite radicals [4] Epicatechin and rutin are strongradical scavengers and inhibitors of lipid peroxidation in vitro[74] Because of oxidation on the B ring of flavonoids havingcatechol group a fairly stable orthosemiquinone radical isformed which is strong scavengers Flavones lacking catecholsystem on oxidation lead to formation of unstable radicalsexhibit weak scavenging potential [75] The literature showsthat flavonoids having an unsaturated 2-3 bond in conju-gation with a 4-oxo function are more potent antioxidantsthan the flavonoids lacking one or both features Conjugationbetween the A and B rings allows a resonance effect ofthe aromatic nucleus that provides stability to the flavonoidradical Free radical scavenging by flavonoids is potentiatedby the presence of both the elements besides other structuralfeatures [76]

The flavonoid heterocycle contributes to antioxidantactivity by permitting conjugation between the aromaticrings and the presence of a free 3-OH Removal of a 3-OH annuls coplanarity and conjugation which compromisesscavenging ability [77] It is proposed that B ring OH groups

form hydrogen bonds with the 3-OH aligning the B ringwith the heterocycle and A ring Due to this intramolecularhydrogen bonding the influence of a 3-OH is enhanced bythe presence of a 3101584041015840-catechol elucidating the potent antiox-idant activity of flavan-3-ols and flavon-3-ols that possess thelatter feature Generally O-methylation of hydroxyl groups offlavonoids decreases their radical scavenging capacity [76]

Occurrence position structure and total number ofsugar moieties in flavonoid (flavonoids glycosides) playan important role in antioxidant activity Aglycones aremore potent antioxidants than their corresponding glyco-sides There are reports that the antioxidant properties offlavonol glycosides from tea declined as the number ofglycosidic moieties increased [78] Though glycosides areusually weaker antioxidants than aglycones bioavailabilityis sometimes enhanced by a glucose moiety In the dietflavonoid glycosidic moieties occur most frequently at the3- or 7-position [79] Increasing degree of polymerizationenhances the effectiveness of procyanidins against a vari-ety of radical species Procyanidin dimers and trimers aremore effective thanmonomeric flavonoids against superoxideanion Tetramers exhibit greater activity against peroxyni-trite and superoxide mediated oxidation than trimers whileheptamers and hexamers demonstrate significantly greatersuperoxide scavenging properties than trimers and tetramers[80]

52 Hepatoprotective Activity Several flavonoids such ascatechin apigenin quercetin naringenin rutin and venoru-ton are reported for their hapatoprotective activities [81]Different chronic diseases such as diabetes may lead to devel-opment of hepatic clinicalmanifestations glutamate-cysteineligase catalytic subunit (Gclc) expression glutathione andROS levels are reported to be decreased in liver of diabeticmice Anthocyanins have drawn increasing attention becauseof their preventive effect against various diseases Zhu etal [82] demonstrated that anthocyanin cyanidin-3-O-120573-glucoside (C3G) increases hepaticGclc expression by increas-ing cAMP levels to activate protein kinase A (PKA) which


in turn upregulates cAMP response element binding protein(CREB) phosphorylation to promote CREB-DNA bindingand increase Gclc transcription Increased Gclc expressionresults in a decrease in hepatic ROS levels and proapop-totic signaling Furthermore C3G treatment lowers hepaticlipid peroxidation inhibits the release of proinflammatorycytokines and protects against the development of hepaticsteatosis [82]

Silymarin is a flavonoids having three structural com-ponents silibinin silydianine and silychristine extractedfrom the seeds and fruit of milk thistle Silybum marianum(Compositae) Silymarin has been reported to stimulateenzymatic activity of DNA-dependent RNA polymerase 1and subsequent biosynthesis of RNA and protein resultingin DNA biosynthesis and cell proliferation leading to liverregeneration only in damaged livers [83] Silymarin increasesproliferating hepatocytes in response to FB1 (Fumonisin B1a mycotoxin produced by Fusarium verticillioides) inducedcell death without modulation of cell proliferation in normallivers The pharmacological properties of silymarin involvethe regulation of cell membrane permeability and integrityinhibition of leukotriene ROS scavenging suppression ofNF-120581B activity depression of protein kinases and collagenproduction [84] Silymarin has clinical applications in thetreatment of cirrhosis ischemic injury and toxic hepatitisinduced by various toxins such as acetaminophen and toxicmushroom [85]

Hepatoprotective activities were observed in flavonoidsisolated from Laggera alata against carbon-tetrachloride(CCl4-) induced injury in primary cultured neonatal rat

hepatocytes and in rats with hepatic damage Flavonoidsat a concentration range of 1ndash100 120583gmL improved cell via-bility and inhibited cellular leakage of hepatocyte aspartateaminotransferase (AST) and alanine aminotransferase (ALT)caused by CCl

4[86] Similarly in an in vivo experiment

flavonoids at of 50 100 and 200mgkg oral doses significantlyreduced the levels of AST ALT total protein and albumin inserum and the hydroxyproline and sialic acid levels in liverHistopathological examinations also revealed the improve-ment in damaged liver with the treatment of flavonoid [86]

Several clinical investigations have shown the efficacy andsafety of flavonoids in the treatment of hepatobiliary dysfunc-tion and digestive complaints such as sensation of fullnessloss of appetite nausea and abdominal pain Equisetumarvense flavonoids as well as hirustrin and avicularin isolatedfrom some other sources is reported to provide protectionagainst chemically induced hepatotoxicity in HepG2 cells[87 88]

53 Antibacterial Activity Flavonoids are known to be syn-thesized by plants in response to microbial infection thusit should not be surprising that they have been found invitro to be effective antimicrobial substances against a widearray of microorganisms Flavonoid rich plant extracts fromdifferent species have been reported to possess antibacterialactivity [70 72 89 90] Several flavonoids including api-genin galangin flavone and flavonol glycosides isoflavonesflavanones and chalcones have been shown to possess potentantibacterial activity [91]

Antibacterial flavonoidsmight be havingmultiple cellulartargets rather than one specific site of action One oftheir molecular actions is to form complex with proteinsthrough nonspecific forces such as hydrogen bonding andhydrophobic effects as well as by covalent bond formationThus their mode of antimicrobial action may be relatedto their ability to inactivate microbial adhesins enzymescell envelope transport proteins and so forth Lipophilicflavonoids may also disrupt microbial membranes [92 93]

Catechins the most reduced form of the C3 unit inflavonoid compounds have been extensively researched dueto their antimicrobial activityThese compounds are reportedfor their in vitro antibacterial activity against Vibrio choleraeStreptococcus mutans Shigella and other bacteria [94 95]The catechins have been shown to inactivate cholera toxinin Vibrio cholera and inhibit isolated bacterial glucosyltrans-ferases in S mutans probably due to complexing activities[94 96] Robinetin myricetin and (minus)-epigallocatechin areknown to inhibit DNA synthesis in Proteus vulgaris Moriet al [97] suggested that the B ring of the flavonoids mayintercalate or form hydrogen bond with the stacking ofnucleic acid bases and further lead to inhibition of DNAand RNA synthesis in bacteria Another study demonstratedinhibitory activity of quercetin apigenin and 3673101584041015840-pentahydroxyflavone against Escherichia coli DNA gyrase[98]

Naringenin and sophoraflavanone G have intensiveantibacterial activity against methicilline resistant Staphy-lococcus aureus (MRSA) and streptococci An alterationof membrane fluidity in hydrophilic and hydrophobicregions may be attributed to this effect which suggests thatthese flavonoids might reduce the fluidity of outer andinner layers of membranes [99] The correlation betweenantibacterial activity and membrane interference supportsthe theory that flavonoids may demonstrate antibacterialactivity by reducing membrane fluidity of bacterial cellsThe 57-dihydroxylation of the A ring and 2101584041015840-or 2101584061015840-dihydroxylation of the B ring in the flavanone structure isimportant for anti-MRSA activity [100] A hydroxyl groupat position 5 in flavanones and flavones is important fortheir activity against MRSA Substitution with C8 andC10 chains may also enhance the antistaphylococcal activ-ity of flavonoids belonging to the flavan-3-ol class [101]Osawa et al have shown that 5-hydroxyflavanones and 5-hydroxyisoflavanones with one two or three additionalhydroxyl groups at the 7 21015840 and 41015840 positions inhibited thegrowth of S mutans and Streptococcus sobrinus [102]

Haraguchi and colleagues [100] studied antibacterialactivity of two flavonoids licochalcones A and C isolatedfrom the roots of Glycyrrhiza inflata against S aureusand Micrococcus luteus They observed that licochalcone Ainhibited incorporation of radioactive precursors intomacro-molecules (DNARNA and protein)This activitywas similarto the mode of action of antibiotics inhibiting respiratorychain since energy is required for active uptake of variousmetabolites as well as for biosynthesis of macromoleculesAfter further studies it was suggested that the inhibitionsite of these flavonoids was between CoQ and cytochrome119888 in the bacterial respiratory electron transport chain [100]


There are many examples that lend support to the prowess ofphytoconstituents derived from edible and medicinal plantsas potent antibacterial agents [103ndash105]

54 Anti-Inflammatory Activity Inflammation is a normalbiological process in response to tissue injury microbialpathogen infection and chemical irritation Inflammation isinitiated by migration of immune cells from blood vesselsand release of mediators at the site of damage This processis followed by recruitment of inflammatory cells releaseof ROS RNS and proinflammatory cytokines to eliminateforeign pathogens and repairing injured tissues In generalnormal inflammation is rapid and self-limiting but aber-rant resolution and prolonged inflammation cause variouschronic disorders [106]

The immune system can be modified by diet phar-macologic agents environmental pollutants and naturallyoccurring food chemicals Certain members of flavonoidssignificantly affect the function of the immune system andinflammatory cells [107] A number of flavonoids such ashesperidin apigenin luteolin and quercetin are reported topossess anti-inflammatory and analgesic effects Flavonoidsmay affect specifically the function of enzyme systems crit-ically involved in the generation of inflammatory processesespecially tyrosine and serine-threonine protein kinases [108109] The inhibition of kinases is due to the competitivebinding of flavonoids with ATP at catalytic sites on theenzymes These enzymes are involved in signal transductionand cell activation processes involving cells of the immunesystem It has been reported that flavonoids are able to inhibitexpression of isoforms of inducible nitric oxide synthasecyclooxygenase and lipooxygenase which are responsible forthe production of a great amount of nitric oxide prostanoidsleukotrienes and other mediators of the inflammatory pro-cess such as cytokines chemokines or adhesion molecules[110] Flavonoids also inhibit phosphodiesterases involvedin cell activation Much of the anti-inflammatory effect offlavonoid is on the biosynthesis of protein cytokines thatmediate adhesion of circulating leukocytes to sites of injuryCertain flavonoids are potent inhibitors of the productionof prostaglandins a group of powerful proinflammatorysignaling molecules [111]

Reversal of the carrageenan induced inflammatory chan-ges has been observed with silymarin treatment It hasbeen found that quercetin inhibit mitogen stimulated immu-noglobulin secretion of IgG IgM and IgA isotypes in vitro[112] Several flavonoids are reported to inhibit plateletadhesion aggregation and secretion significantly at 1ndash10mMconcentration [113] The effect of flavonoid on platelets hasbeen related to the inhibition of arachidonic acid metabolismby carbon monoxide [114] Alternatively certain flavonoidsare potent inhibitors of cyclic AMP phosphodiesterase andthis may in part explain their ability to inhibit plateletfunction

55 Anticancer Activity Dietary factors play an importantrole in the prevention of cancers Fruits and vegetables havingflavonoids have been reported as cancer chemopreventive

agents [72 115] Consumption of onions andor apples twomajor sources of the flavonol quercetin is inversely associatedwith the incidence of cancer of the prostate lung stomachand breast In addition moderate wine drinkers also seem tohave a lower risk to develop cancer of the lung endometriumesophagus stomach and colon [116]The critical relationshipof fruit and vegetable intake and cancer prevention has beenthoroughly documented It has been suggested that majorpublic health benefits could be achieved by substantiallyincreasing consumption of these foods [117]

Several mechanisms have been proposed for the effectof flavonoids on the initiation and promotion stages of thecarcinogenicity including influences on development andhormonal activities [118] Major molecular mechanisms ofaction of flavonoids are given as follows

(1) downregulation of mutant p53 protein(2) cell cycle arrest(3) tyrosine kinase inhibition(4) inhibition of heat shock proteins(5) estrogen receptor binding capacity(6) inhibition of expression of Ras proteins

Mutations of p53 are among the most common geneticabnormalities in human cancersThe inhibition of expressionof p53 may lead to arrest the cancer cells in the G2-Mphase of the cell cycle Flavonoids are found to downregulateexpression ofmutant p53 protein to nearly undetectable levelsin human breast cancer cell lines [119] Tyrosine kinases area family of proteins located in or near the cell membraneinvolved in the transduction of growth factor signals tothe nucleus Their expression is thought to be involved inoncogenesis via an ability to override normal regulatorygrowth control Drugs inhibiting tyrosine kinase activity arethought to be possible antitumor agents without the cytotoxicside effects seen with conventional chemotherapy Quercetinwas the first tyrosine kinase inhibiting compound tested ina human phase I trial [120] Heat shock proteins form acomplex with mutant p53 which allows tumor cells to bypassnormal mechanisms of cell cycle arrest Heat shock proteinsalso allow for improved cancer cell survival under differentbodily stresses Flavonoids are known to inhibit production ofheat shock proteins in several malignant cell lines includingbreast cancer leukemia and colon cancer [119]

Recently it has been shown that the flavanol epigallocate-chin-3-gallate inhibited fatty acid synthase (FAS) activity andlipogenesis in prostate cancer cells an effect that is stronglyassociated with growth arrest and cell death [116 121] Incontrast tomost normal tissues expression of FAS ismarkedlyincreased in various human cancers Upregulation of FASoccurs early in tumor development and is further enhancedin more advanced tumors [122]

Quercetin is known to produce cell cycle arrest in pro-liferating lymphoid cells In addition to its antineoplasticactivity quercetin exerted growth-inhibitory effects on sev-eral malignant tumor cell lines in vitro These included P-388 leukemia cells gastric cancer cells (HGC-27 NUGC-2NKN-7 andMKN-28) colon cancer cells (COLON 320DM)


humanbreast cancer cells human squamous and gliosarcomacells and ovarian cancer cells [119] Markaverich et al [123]proposed that tumor cell growth inhibition by quercetinmay be due to its interaction with nuclear type II estrogenbinding sites (EBS) It has been experimentally proved thatincreased signal transduction in human breast cancer cells ismarkedly reduced by quercetin acting as an antiproliferativeagent [124]

Barnes [125] has extensively reviewed the anticancereffects of genistein on in vitro and in vivo models In anstudy to determine effects of isoflavones genistein daidzeinand biochanin A on mammary carcinogenesis genistein wasfound to suppress the development of chemically inducedmammary cancer without reproductive or endocrinologicaltoxicities Neonatal administration of genistein (a flavonoid)exhibited a protective effect against the subsequent develop-ment of induced mammary cancer in rats [126] Hesperidina flavanone glycoside is known to inhibit azoxymethanolinduced colon and mammary cancers in rats [127] Theanticancer properties of flavonoids contained in citrus fruitshave been reviewed by Carroll et al [128] Several flavonolsflavones flavanones and the isoflavone biochanin A arereported to have potent antimutagenic activity [129] Acarbonyl function at C-4 of the flavone nucleus was found tobe essential for their activity Flavone-8-acetic acid has alsobeen shown to have antitumor effects [130] In earlier studiesellagic acid robinetin quercetin and myricetin have beenshown to inhibit the tumorigenicity of BP-7 8-diol-9 and 10-epoxide-2 on mouse skin [131]

Higher consumption of phytoestrogens includingisoflavones and other flavonoids has been shown to provideprotection against prostate cancer risk [132] It is well knownthat due to oxidative stress cancer initiation may take placeand thus potent antioxidants show potential to combatprogression of carcinogenesis Potential of antioxidantas an anticancer agent depends on its competence as anoxygen radical inactivator and inhibitor [70 72 133]Therefore diets rich in radical scavengers would diminish thecancer-promoting action of some radicals [134]

56 Antiviral Activity Natural compounds are an importantsource for the discovery and the development of novel antivi-ral drugs because of their availability and expected low sideeffects Naturally occurring flavonoids with antiviral activityhave been recognized since the 1940s and many reportson the antiviral activity of various flavonoids are availableSearch of effective drug against human immunodeficiencyvirus (HIV) is the need of hour Most of the work related withantiviral compounds revolves around inhibition of variousenzymes associated with the life cycle of viruses Structurefunction relationship between flavonoids and their enzymeinhibitory activity has been observed Gerdin and Srensso[135] demonstrated that flavan-3-o1 was more effective thanflavones and flavonones in selective inhibition ofHIV-1 HIV-2 and similar immunodeficiency virus infections Baicalin aflavonoid isolated from Scutellaria baicalensis (Lamieaceae)inhibits HIV-1 infection and replication Baicalein and otherflavonoids such as robustaflavone and hinokiflavone have

Table 4 Antiviral activity of various flavonoids

Flavonoid Virus References

QuercetinRabies virus herpes virusparainfluenza virus polio virusmengo virus and pseudorabiesvirus

[32 33]

Rutin Parainfluenza virus influenza virusand potato virus [34]

ApigeninImmunodeficiency virus infectionHerpes simplex virus type andAuzesky virus

[35]

Naringin Respiratory syncytial virus [36]Luteolin Auzesky virus [37]Morin Potato virus [38]Galangin Herpes simplex virus type [39]

also been shown to inhibit HIV-1 reverse transcriptase [136]Another study revealed inhibition of HIV-1 entry into cellsexpressing CD4 and chemokine coreceptors and antagonismof HIV-1 reverse transcriptase by the flavone O-glycoside[137] Catechins are also known to inhibit DNA polymerasesof HIV-1 Flavonoid such as demethylated gardenin A androbinetin are known to inhibit HIV-1 proteinase [136] It hasalso been reported that the flavonoids chrysin acacetin andapigenin preventHIV-1 activation via a novelmechanism thatprobably involves inhibition of viral transcription [138]

Various combinations of flavones and flavonols havebeen shown to exhibit synergism Kaempferol and luteolinshow synergistic effect against herpes simplex virus (HSV)Synergism has also been reported between flavonoids andother antiviral agents Quercetin is reported to potentiate theeffects of 5-ethyl-2-dioxyuridine and acyclovir against HSVand pseudorabies infection [136] Studies have displayed thatflavonols aremore active than flavones against herpes simplexvirus type 1 and the activity order was found to be galanginkaempferol and quercetin [136]

Zandi et al [139] studied the antidengue virus propertiesof quercetin hesperetin naringin and daidzein at differ-ent stages of DENV-2 (dengue virus type-2) infection andreplication cycle Quercetin was found to be most effectiveagainst DENV-2 in Vero cells Many flavonoids namelydihydroquercetin dihydrofisetin leucocyanidin pelargoni-din chloride and catechin show activity against several typesof virus includingHSV respiratory syncytial virus polio virusand Sindbis virus [135] Inhibition of viral polymerase andbinding of viral nucleic acid or viral capsid proteins havebeen proposed as antiviral mechanisms of action [139] Listof some flavonoids and their efficacy against viruses is givenin Table 4

6 Role of Flavonoids in Plants

61 Combating Oxidative Stress Flavonoids have long beenreported as servingmultiple functions in plants [140] Variousabiotic and biotic factors helps in the generation of ROSin plants leading to oxidative stress Flavonoid biosynthesis


in plants is almost exclusively enhanced due to oxidativestress They have capacity to absorb the most energetic solarwavelengths (ie UV-B and UV-A) inhibit the generation ofROS and quench ROS once they are formed [141] Flavonoidsdischarged primary UV-B screening functions when earlyplants moved from water to colonize the land Extent ofantioxidant capacity and ability to absorb UV-wavelengthsdepends upon the nature of substitution on different ringsof flavonoids Dihydroxy B ring substituted flavonoids have agreater antioxidant capacity while their monohydroxy B ringsubstituted counterparts have greater ability to absorb UV-wavelengths [141]

The most reactive hydroxyl groups (7-OH in flavones orthe 3-OH in flavonols) in flavonoids are generally glycosy-lated Glycosylation increases solubility in the aqueous cellu-lar environment protects the reactive hydroxyl groups fromautooxidation [142] and allows the transport of flavonoidsfrom the endoplasmic reticulum to various cellular com-partments and their secretion to the plasma membrane andthe cell wall [143] Recent evidence shows that antioxidantflavonoids are located in the nucleus of mesophyll cells andwithin centers of ROS generation that is the chloroplastHere they can easily quench H

2O2 hydroxyl radical and

singlet oxygen [141 144]Oxidative stress due to an excess of excitation energy

in the chloroplast may be aggravated under conditions thatlimit the diffusion of CO

2to the carboxylation sites and

the efficiency of carboxylation [141 145] The environmentallimitations to CO

2assimilation rate include droughtsalinity

lowhigh temperature and nutrient scarcity Under theseconditions the activity of ROS detoxifying enzymes may sig-nificantly reduce in the chloroplast [146 147] which in turnupregulates the biosynthesis of ROS scavenging flavonoidsThe reducing functions of flavonoids are of key significancein plants under severe stress conditions These functionalroles are concomitant with the very high concentration ofdihydroxy B ring substituted flavonoids [148] Flavonoidshave been suggested as representing a secondary antioxidantdefense system in plant tissues exposed to different stresses[141] Lipid peroxidation is the common consequence ofoxidative stress which disrupts the cell membrane integrityQuercetin 3-O-rutinoside (rutin) may interact with the polarhead of phospholipids at water lipid interface enhancingmembrane rigidity and consequently protecting membranesfrom oxidative damage [149]

62 As Growth Regulator Flavonoids carry out functionalroles of amazing significance in plant-environment inter-actions Flavonoids (in the nanomolar range) may regulateauxin movement and catabolism The ability of flavonoidsto create auxin gradients translates into phenotypes withdifferent morphoanatomical features [150] The control offlavonoids on auxin movement may have immense value inthe stress-induced morphogenic responses of plants such asthe flight strategy of sessile organisms exposed to unfavorableenvironments [151] Species rich in dihydroxy flavonoidsexhibit phenotypes with strikingly different morphologi-cal traits as compared with those rich in monohydroxy

flavonoids [152] Dwarf bushy phenotypes with few smalland thick leaves to direct sunlight irradiance are usuallypresent in sunny environments thus protecting leaves locateddeep in the canopy from light-induced severe cellular home-ostasis perturbations On the contrary shaded plants whichare rich in kaempferol andor apigenin derivatives (havingnegligible concentrations of quercetin derivatives) have longinternodes and large leaf lamina coupled with reduced leafthickness [151]

Flavonoids at the plasma membrane are effective inhib-itors of PIN (pin formed) and MDR (multidrug resistance)glycoproteins that are involved in the cell to cell movementof auxin The ability of flavonoids to inhibit the activityof the efflux facilitator PIN and MDR proteins dependson the presence of the catechol group in the B ring ofthe flavonoid skeleton In addition flavonoids regulate theactivity of IAA-oxidase with markedly different effects basedon their chemical structure [153] Recent evidence of anuclear location of flavonoids (as well as of enzymes offlavonoid biosynthesis) supports that flavonoids are capableof modulating the activity of proteins involved in cell growthFlavonoids may therefore act as transcriptional regulators[154 155]

7 Microbial Production of Flavonoids

In response to the low production efficiency from plantsand chemical synthesis research groups have directed theirattention to the production of flavonoids in microorganismsusing metabolic engineering and synthetic biology [156]Chemical synthesis of flavonoids requires extreme reactionconditions and toxic chemicals [157] Because of the rapiddevelopment in molecular biology tools and the flooding ofgenome information from a variety of organisms combi-natorial biosynthesis offers an advantage for production ofrare and expensive natural products It can be used in bothsimple and complex transformations without the tiresomeblocking and deblocking steps that are common in organicsynthesis [158] Several prokaryotes and eukaryotes such asE coli Saccharomyces cerevisiae Streptomyces venezuelae andPhellinus igniarius a medicinal mushroom have been usedfor production of flavonoids [12]

71 Phenylpropanoid Pathway In plants naringenin chalconeis the precursor for a large number of flavonoids producedby the phenylpropanoid synthetic pathway Fermentativeproduction by E coli carrying an artificially assembledphenylpropanoid pathway was the first example to showthat a nearly complete biosynthetic pathway in plants wasestablished in a heterologous microorganism for productionof flavanones from the amino acid precursors phenylalanineand tyrosine [159] As the first step in the phenylpropanoidpathway in plants phenylalanine is deaminated to yieldcinnamic acid by the action of phenylalanine ammonia-lyase (PAL) Cinnamic acid is hydroxylated by cinnamate-4-hydroxylase (C4H) to p-coumaric acid which is thenactivated to p-coumaroyl-CoA by the action of 4-coumarateCoA ligase Chalcone synthase (CHS) catalyzes the stepwise


condensation of three acetate units from malonyl-CoA withp-coumaroyl-CoA to yield naringenin chalcone Naringeninchalcone is converted to naringenin by chalcone isomerase(CHI) or nonenzymatically in vitro [160]

72 Enhancement of Flavonoid Production Combination ofpromoter and target genes knockout of related genes over-expression of malonyl-CoA and construction of artificialP450 enzymes are the key molecular biology technology pro-cedures used in the heterologous production of flavonoidsEvery gene from the phenylpropanoid pathway is clonedin the host under the control of the promoter which oftenplays an important role in the heterologous expression ofsecondary metabolites Several promoters have been used toenhance production of flavonoids according to the need ofspecific host such as T7 ermElowast and GAL1 promoter [12]The extremely low concentration of malonyl-CoA in themicrobial cell was one of the drawbacks in the microbio-logical production of flavonoids Through the coordinatedoverexpression of acetyl-CoA carboxylase genes from Pho-torhabdus luminescens intracellular malonyl-CoA pool wasamplified leading to increased production of flavonoids [161]Supplication of UDP-glucose is also a key effector in thebiosynthesis of flavonoids It was proved in an experimentin which researchers knocked out the udg gene encoding forUDP-glucose dehydrogenase This resulted in elimination ofendogenous UDP-glucose consumption pathway leading toincrease in intracellular concentration of UDP-glucose andas a consequence increment in the production of flavanonesand anthocyanins was observed [162]

One of the barriers to the production of flavonoids andtheir related compounds in microorganisms by means ofassembling biosynthetic genes to form an artificial pathwayis the difficulty in expression of active membrane-boundcinnamate-4-hydroxylase [163]This enzyme is not expressedefficiently in bacteria due to its instability and the lackof its cognate cytochrome P450 reductase in the host Anadvantage of flavonoid production in yeasts or fungi is theirability to express functionally active microsomal cytochromeP450 enzymes which are usually difficult to be expressed inan active form in bacterial cellsThere are variousmicrosomalcytochrome P450 enzymes that are involved in the flavonoidbiosynthesis pathway [164] Combining bacterial cells andeukaryotic cells in a pot enabled researchers to generate awider library of natural and unnatural products than anyof the previously reported systems De novo production ofthe key flavonoid intermediate naringenin has been demon-strated for the first time from glucose using an engineered Scerevisiae strain which led to fourfold higher concentrationsthan reported in earlier studies on de novo biosynthesis [165166]

8 Conclusion

Prevention and cure of diseases using phytochemicals espe-cially flavonoids are well known Fruits and vegetables arenatural sources of flavonoids Variety of flavonoids foundin the nature possesses their own physical chemical and

physiological properties Structure function relationship offlavonoids is epitome ofmajor biological activities Medicinalefficacy ofmany flavonoids as antibacterial hepatoprotectiveanti-inflammatory anticancer and antiviral agents is wellestablished These substances are more commonly used inthe developing countriesTherapeutic use of new compoundsmust be validated using specific biochemical tests With theuse of genetic modifications it is now possible to produceflavonoids at large scale Further achievements will providenewer insights andwill certainly lead to a new era of flavonoidbased pharmaceutical agents for the treatment of manyinfectious and degenerative diseases

Conflict of Interests

The authors declare that they do not have any conflict ofinterests

Acknowledgment

Shashank Kumar acknowledges financial support fromUGCIndia in the form of Rajiv Gandhi National Senior Researchfellowship

References

[1] M F Mahomoodally A Gurib-Fakim and A H SubrattyldquoAntimicrobial activities and phytochemical profiles of endemicmedicinal plants of Mauritiusrdquo Pharmaceutical Biology vol 43no 3 pp 237ndash242 2005

[2] A K Pandey ldquoAnti-staphylococcal activity of a pan-tropicalaggressive and obnoxious weed Parihenium histerophorus an invitro studyrdquo National Academy Science Letters vol 30 no 11-12pp 383ndash386 2007

[3] R A Dixon P M Dey and C J Lamb ldquoPhytoalexinsenzymology and molecular biologyrdquo Advances in Enzymologyand Related Areas of Molecular Biology vol 55 pp 1ndash136 1983

[4] E H Kelly R T Anthony and J B Dennis ldquoFlavonoid antiox-idants chemistry metabolism and structure-activity relation-shipsrdquo Journal of Nutritional Biochemistry vol 13 no 10 pp572ndash584 2002

[5] S Kumar A Mishra and A K Pandey ldquoAntioxidant mediatedprotective effect of Parthenium hysterophorus against oxidativedamage using in vitro modelsrdquo BMC Complementary andAlternative Medicine vol 13 article 120 2013

[6] S Kumar and A K Pandey ldquoPhenolic content reducing powerand membrane protective activities of Solanum xanthocarpumroot extractsrdquo Vegetos vol 26 pp 301ndash307 2013

[7] M Leopoldini N Russo S Chiodo and M Toscano ldquoIronchelation by the powerful antioxidant flavonoid quercetinrdquoJournal of Agricultural and Food Chemistry vol 54 no 17 pp6343ndash6351 2006

[8] S Kumar A Gupta and A K Pandey ldquoCalotropis procera rootextract has capability to combat free radical mediated damagerdquoISRN Pharmacology vol 2013 Article ID 691372 8 pages 2013

[9] N C Cook and S Samman ldquoReview flavonoids-chemistrymetabolism cardioprotective effects and dietary sourcesrdquo Jour-nal of Nutritional Biochemistry vol 7 no 2 pp 66ndash76 1996


[10] C A Rice-Evans N J Miller P G Bolwell P M Broamleyand J B Pridham ldquoThe relative antioxidant activities of plant-derived polyphenolic flavonoidsrdquo Free Radical Research vol 22no 4 pp 375ndash383 1995

[11] G Agati E Azzarello S Pollastri and M Tattini ldquoFlavonoidsas antioxidants in plants location and functional significancerdquoPlant Science vol 196 pp 67ndash76 2012

[12] F Du F Zhang F Chen et al ldquoAdvances in microbial heterolo-gous production of flavonoidsrdquo African Journal of MicrobiologyResearch vol 5 no 18 pp 2566ndash2574 2011

[13] E J Middleton ldquoEffect of plant flavonoids on immune andinflammatory cell functionrdquoAdvances in ExperimentalMedicineand Biology vol 439 pp 175ndash182 1998

[14] M Lopez F Martinez C Del Valle C Orte and M MiroldquoAnalysis of phenolic constituents of biological interest in redwines by high-performance liquid chromatographyrdquo Journal ofChromatography A vol 922 no 1-2 pp 359ndash363 2001

[15] Y Hara S J Luo R L Wickremasinghe and T YamanishildquoSpecial issue on teardquo Food Reviews International vol 11 pp371ndash542 1995

[16] S Kreft M Knapp and I Kreft ldquoExtraction of rutin frombuckwheat (Fagopyrum esculentum Moench) seeds and deter-mination by capillary electrophoresisrdquo Journal of Agriculturaland Food Chemistry vol 47 no 11 pp 4649ndash4652 1999

[17] A J Stewart S Bozonnet W Mullen G I Jenkins M ELean and A Crozier ldquoOccurrence of flavonols in tomatoesand tomato-based productsrdquo Journal of Agricultural and FoodChemistry vol 48 no 7 pp 2663ndash2669 2000

[18] M G L Hertog P C H Hollman and M B Katan ldquoContentof potentially anticarcinogenic flavonoids of 28 vegetables and9 fruits commonly consumed in the Netherlandsrdquo Journal ofAgricultural and Food Chemistry vol 40 no 12 pp 2379ndash23831992

[19] Y Miyake K Shimoi S Kumazawa K Yamamoto N Kinaeand T Osawa ldquoIdentification and antioxidant activity offlavonoid metabolites in plasma and urine of eriocitrin-treatedratsrdquo Journal of Agricultural and Food Chemistry vol 48 no 8pp 3217ndash3224 2000

[20] R L Rousseff S F Martin and C O Youtsey ldquoQuantitativesurvey of narirutin naringin hesperidin and neohesperidin incitrusrdquo Journal of Agricultural and Food Chemistry vol 35 no6 pp 1027ndash1030 1987

[21] K Reinli and G Block ldquoPhytoestrogen content of foods acompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996

[22] M L Lazaro ldquoDistribution and biological activities of theflavonoid luteolinrdquo Mini-Reviews in Medicinal Chemistry vol9 no 1 pp 31ndash59 2009

[23] E Tripoli M L Guardia S Giammanco D D Majo and MGiammanco ldquoCitrus flavonoids molecular structure biologicalactivity and nutritional properties a reviewrdquo Food Chemistryvol 104 no 2 pp 466ndash479 2007

[24] K K Gupta S C Taneja K L Dhar andC K Atal ldquoFlavonoidsof Andrographis paniculatardquo Phytochemistry vol 22 no 1 pp314ndash315 1983

[25] A Murlidhar K S Babu T R Sankar P Redenna G V Reddyand J Latha ldquoAntiinflammatory activity of flavonoid fractionisolated from stem bark of Butea monosperma (Lam) a mecha-nism based studyrdquo International Journal of Phytopharmacologyvol 1 pp 124ndash132 2010

[26] M A Aderogba A O Ogundaini and J N Eloff ldquoIsolationof two flavonoids from Bauhinia monandra leaves and theirantioxidative effectsrdquo The African Journal of Traditional Com-plementary and Alternative Medicines vol 3 no 4 pp 59ndash652006

[27] S Sankaranarayanan P Bama J Ramachandran et al ldquoEthnob-otanical study of medicinal plants used by traditional users inVillupuram district of Tamil Nadu Indiardquo Journal of MedicinalPlant Research vol 4 no 12 pp 1089ndash1101 2010

[28] M Sannomiya V B Fonseca M A D Silva et al ldquoFlavonoidsand antiulcerogenic activity from Byrsonima crassa leavesextractsrdquo Journal of Ethnopharmacology vol 97 no 1 pp 1ndash62005

[29] K Kogawa K Kazuma N Kato N Noda and M SuzukildquoBiosynthesis of malonylated flavonoid glycosides on basis ofmalonyl transferase activity in the petals of Clitoria ternateardquoJournal of Plant Physiology vol 164 no 7 pp 886ndash894 2007

[30] S Ghoulami A I Idrissi and S Fkih-Tetouani ldquoPhytochemicalstudy ofMentha longifolia of Moroccordquo Fitoterapia vol 72 no5 pp 596ndash598 2001

[31] M Agarwal and R Kamal ldquoStudies on flavonoid productionusing in-vitro cultures ofMomordica charantiardquo Indian Journalof Biotechnology vol 6 no 2 pp 277ndash279 2007

[32] S A Ghazal M Abuzarqua and A M Mahansneh ldquoEffect ofplant flavonoids on immune and inflammatory cell functionrdquoPhototherapy Research vol 2 pp 265ndash271 1992

[33] K P Kell A M Manadi Z F Adiyasora R M Kunaera I ZV Akad and S S R Naun ldquoBioflavonoids and health effects inmanrdquo Chemical Abstracts vol 107 pp 366ndash367 1987

[34] R T Deca I J Gouzalez T M V Mactinez J Moreno andS C A Romo ldquoSoil bioI In vitro antifungal activity of someflavonoids and their metabolitesrdquo Biochemistry vol 19 pp 223ndash231 1987

[35] Y Tsuchiya M Shimizu Y Hiyama et al ldquoInhibitory effect offlavonoids on fungal diseasesrdquo Chemical and PharmaceuticalBulletin vol 33 pp 3881ndash3890 1985

[36] M Bakay I Mucsi I Beladi and M M Gabor ldquoAntiviralflavonoids from Alkena orientalisrdquo Acta Microbiologica vol 15pp 223ndash232 1968

[37] K Hayashi T Hayashi M Arisawa and N Morita ldquoIn vitroinhibition of viral disease by flavonoidsrdquo Antiviral Chemistryand Chemotherapy vol 4 no 1 pp 49ndash53 1993

[38] V D Tripathi and R P Rastogi ldquoIn vitro anti-HIV activityof flavonoids isolated from Garcinia multifoliardquo Journal ofScientific and Industrial Research vol 40 pp 116ndash121 1981

[39] U P Singh V B Pandey K N Singh and R O N SinghldquoStructural and biogenic relationships of isoflavonoidsrdquo Cana-dian Journal of Botany vol 166 pp 1901ndash1910 1988

[40] K R Narayana M S Reddy M R Chaluvadi and D RKrishna ldquoBioflavonoids classification pharmacological bio-chemical effects and therapeutic potentialrdquo Indian Journal ofPharmacology vol 33 no 1 pp 2ndash16 2001

[41] E Middleton ldquoThe flavonoidsrdquo Trends in PharmacologicalSciences vol 5 pp 335ndash338 1984

[42] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004

[43] C A Rice-Evans N J Miller and G Paganga ldquoStructure-antioxidant activity relationships of flavonoids and phenolicacidsrdquo Free Radical Biology andMedicine vol 20 no 7 pp 933ndash956 1996


[44] E Wollenweber and V H Dietz ldquoOccurrence and distributionof free flavonoid aglycones in plantsrdquo Phytochemistry vol 20no 5 pp 869ndash932 1981

[45] RKoesWVerweij and FQuattrocchio ldquoFlavonoids a colorfulmodel for the regulation and evolution of biochemical path-waysrdquo Trends in Plant Sciences vol 10 no 5 pp 236ndash242 2005


[47] I C W Arts V B Putte and P C H Hollman ldquoCatechincontents of foods commonly consumed in the Netherlands 1Fruits vegetables staple foods and processed foodsrdquo Journal ofAgricultural and Food Chemistry vol 48 no 5 pp 1746ndash17512000

[48] A Gil-Izquierdo M I Gil F Ferreres and F A Tomas-Barberan ldquoIn vitro availability of flavonoids and other phenolicsin orange juicerdquo Journal of Agricultural and Food Chemistry vol49 no 2 pp 1035ndash1041 2001

[49] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80pp 1073ndash1080 2000

[50] F Pourmorad S J Hosseinimehr andN Shahabimajd ldquoAntiox-idant activity phenol and flavonoid contents of some selectedIranian medicinal plantsrdquoThe African Journal of Biotechnologyvol 5 no 11 pp 1142ndash1145 2006

[51] S Kumar and A K Pandey ldquoAntioxidant lipo-protective andantibacterial activities of phytoconstituents present in Solanumxanthocarpum rootrdquo International Review of Biophysical Chem-istry vol 3 no 3 pp 42ndash47 2012

[52] B Fuhrman S Buch and J Vaya ldquoLicorice extract and itsmajorpolyphenol glabridin protect low-density lipoprotein againstlipid peroxidation in vitro and ex vivo studies in humans and inatherosclerotic apolipoprotein E-deficient micerdquoThe AmericanJournal of Clinical Nutrition vol 66 no 2 pp 267ndash275 1997

[53] W J Craig ldquoHealth-promoting properties of common herbsrdquoThe American Journal of Clinical Nutrition vol 70 no 3 pp491ndash499 1999

[54] S Kumar U K Sharma A K Sharma and A K Pandey ldquoPro-tective efficacy of Solanum xanthocarpum root extracts againstfree radical damage phytochemical analysis and antioxidanteffectrdquo Cellular andMolecular Biology vol 58 no 1 pp 171ndash1782012

[55] J X Li B Xue Q Chai Z X Liu A P Zhao and LB Chen ldquoAntihypertensive effect of total flavonoid fractionof Astragalus complanatus in hypertensive ratsrdquo The ChineseJournal of Physiology vol 48 no 2 pp 101ndash106 2005

[56] D Commenges V Scotet S Renaud H Jacqmin-Gadda PBarberger-Gateau and J F Dartigues ldquoIntake of flavonoids andrisk of dementiardquoTheEuropean Journal of Epidemiology vol 16no 4 pp 357ndash363 2000

[57] B H Havsteen ldquoThe biochemistry and medical significance ofthe flavonoidsrdquo Pharmacology andTherapeutics vol 96 no 2-3pp 67ndash202 2002

[58] P C H Hollman M N C P Buijsman Y van Gameren P JCnossen J H M de Vries and M B Katan ldquoThe sugar moietyis a major determinant of the absorption of dietary flavonoidglycosides inmanrdquo Free Radical Research vol 31 no 6 pp 569ndash573 1999

[59] A J Day F J Canada J C Diaz et al ldquoDietary flavonoid andisoflavone glycosides are hydrolysed by the lactase site of lactase

phlorizin hydrolaserdquo FEBS Letters vol 468 no 2-3 pp 166ndash1702000

[60] TWalle ldquoSerial review flavonoids and isoflavones (phytoestro-gens absorption metabolism and bioactivity) absorption andmetabolism of flavonoidsrdquo Free Radical Biology and Medicinevol 36 no 7 pp 829ndash837 2004

[61] R R Scheline ldquoMetabolism of foreign compounds by gastroin-testinal microorganismsrdquo Pharmacological Reviews vol 25 no4 pp 451ndash532 1973

[62] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998

[63] P C H Hollman ldquoAbsorption bioavailability and metabolismof flavonoidsrdquo Pharmaceutical Biology vol 42 pp 74ndash83 2004

[64] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997

[65] J E Spencer F Chaudry A S Pannala S K Srai E Debnamand E C Rice ldquoDecomposition of cocoa procyanidins in thegastric milieurdquo Biochemical and Biophysical Research Commu-nications vol 272 no 1 pp 236ndash241 2000

[66] I F F Benzie Y T Szeto J J Strain and B TomlinsonldquoConsumption of green tea causes rapid increase in plasmaantioxidant power in humansrdquo Nutrition and Cancer vol 34no 1 pp 83ndash87 1999

[67] A K Pandey A K Mishra and A Mishra ldquoAntifungal andantioxidative potential of oil and extracts derived from leavesof Indian spice plant Cinnamomum tamalardquo Cellular andMolecular Biology vol 58 pp 142ndash147 2012

[68] G Cao E Sofic and R L Prior ldquoAntioxidant and prooxidantbehavior of flavonoids structure-activity relationshipsrdquo FreeRadical Biology and Medicine vol 22 no 5 pp 749ndash760 1997

[69] B Halliwell and JM C Gutteridge Free Radicals in Biology andMedicine Oxford University Press Oxford UK 1998

[70] A Mishra S Kumar and A K Pandey ldquoScientific validationof the medicinal efficacy of Tinospora cordifoliardquoThe ScientificWorld Journal vol 2013 Article ID 292934 2013

[71] J E Brown H Khodr R C Hider and C Rice-EvansldquoStructural dependence of flavonoid interactions with Cu2+ions implications for their antioxidant propertiesrdquo BiochemicalJournal vol 330 no 3 pp 1173ndash1178 1998

[72] A Mishra A K Sharma S Kumar A K Saxena and A KPandey ldquoBauhinia variegata leaf extracts exhibit considerableantibacterial antioxidant and anticancer activitiesrdquo BioMedResearch International vol 2013 Article ID 915436 10 pages2013

[73] A Van S A B E van den Berg D J M N J L Tromp et alldquoStructural aspects of antioxidant activity of flavonoidsrdquo FreeRadical Biology and Medicine vol 20 no 3 pp 331ndash342 1996

[74] N L Kerry andM Abbey ldquoRed wine and fractionated phenoliccompounds prepared from redwine inhibit lowdensity lipopro-tein oxidation in vitrordquoAtherosclerosis vol 135 no 1 pp 93ndash1021997

[75] A Sekher Pannala T S Chan P J O Brien and C A Rice-Evans ldquoFlavonoid B-ring chemistry and antioxidant activityfast reaction kineticsrdquo Biochemical and Biophysical ResearchCommunications vol 282 no 5 pp 1161ndash1168 2001



[77] W Bors W Heller C Michel and M Saran ldquoFlavonoids asantioxidants determination of radical-scavenging efficienciesrdquoMethods in Enzymology vol 186 pp 343ndash355 1990

[78] A K Ratty and N P Das ldquoEffects of flavonoids on nonenzy-matic lipid peroxidation structure-activity relationshiprdquo Bio-chemical Medicine and Metabolic Biology vol 39 no 1 pp 69ndash79 1988

[79] P C Hollman M N Bijsman Y van Gameren E P CnossenJ H de Vries and M B Katan ldquoThe sugar moiety is a majordeterminant of the absorption of dietary flavonoid glycosidesin manrdquo Free Radical Research vol 31 no 6 pp 569ndash573 1999

[80] B Vennat M A Bos A Pourrat and P Bastide ldquoProcyanidinsfrom tormentil fractionation and study of the anti-radicalactivity towards superoxide anionrdquo Biological and Pharmaceu-tical Bulletin vol 17 no 12 pp 1613ndash1615 1994

[81] A R Tapas D M Sakarkar and R B Kakde ldquoFlavonoidsas nutraceuticals a reviewrdquo Tropical Journal of PharmaceuticalResearch vol 7 pp 1089ndash1099 2008

[82] WZhuQ Jia YWang Y Zhang andMXia ldquoThe anthocyanincyanidin-3-O-120573-glucoside a flavonoid increases hepatic glu-tathione synthesis and protects hepatocytes against reactiveoxygen species during hyperglycemia involvement of a cAMP-PKA-dependent signaling pathwayrdquo Free Radical Biology andMedicine vol 52 no 2 pp 314ndash327 2012

[83] J Sonnenbichler and I Zetl ldquoBiochemical effects of the flavono-lignan silibinin on RNA protein and DNA synthesis in ratliversrdquo in Progress in Clinical and Biological Research V Cody EMiddleton and J B Karborne Eds vol 213 pp 319ndash331 AlanR Liss New York NY USA 1986

[84] Q He J Kim and R P Sharma ldquoSilymarin protects againstliver damage in balbc mice exposed to fumonisin b1 despiteincreasing accumulation of free sphingoid basesrdquo ToxicologicalSciences vol 80 no 2 pp 335ndash342 2004

[85] R Saller R Meier and R Brignoli ldquoThe use of silymarin in thetreatment of liver diseasesrdquoDrugs vol 61 no 14 pp 2035ndash20632001

[86] YWu FWang Q Zheng et al ldquoHepatoprotective effect of totalflavonoids from Laggera alata against carbon tetrachloride-induced injury in primary cultured neonatal rat hepatocytesand in rats with hepatic damagerdquo Journal of Biomedical Sciencevol 13 no 4 pp 569ndash578 2006

[87] J P E Spencer D Vauzour and C Rendeiro ldquoFlavonoidsand cognition the molecular mechanisms underlying theirbehavioural effectsrdquo Archives of Biochemistry and Biophysicsvol 492 no 1-2 pp 1ndash9 2009

[88] S M Kim K Kang E H Jho et al ldquoHepatoprotective effect offlavonoid glycosides from Lespedeza cuneata against oxidativestress induced by tert-butyl hyperoxiderdquo Phytotherapy Researchvol 25 no 7 pp 1011ndash1017 2011

[89] AMishra S Kumar A Bhargava B Sharma and A K PandeyldquoStudies on in vitro antioxidant and antistaphylococcal activitiesof some important medicinal plantsrdquo Cellular and MolecularBiology vol 57 no 1 pp 16ndash25 2011

[90] A K Pandey A K Mishra A Mishra S Kumar and AChandra ldquoTherapeutic potential of C zeylanicum extracts anantifungal and antioxidant perspectiverdquo International Journal ofBiological and Medical Research vol 1 pp 228ndash233 2010

[91] T P T Cushnie and A J Lamb ldquoAntimicrobial activity offlavonoidsrdquo International Journal of Antimicrobial Agents vol26 no 5 pp 343ndash356 2005

[92] MM Cowan ldquoPlant products as antimicrobial agentsrdquoClinicalMicrobiology Reviews vol 12 no 4 pp 564ndash582 1999

[93] A K Mishra A Mishra H K Kehri B Sharma and A KPandey ldquoInhibitory activity of Indian spice plantCinnamomumzeylanicum extracts against Alternaria solani and Curvularialunata the pathogenic dematiaceousmouldsrdquoAnnals of ClinicalMicrobiology and Antimicrobials vol 8 article 9 2009

[94] R P Borris ldquoNatural products research perspectives from amajor pharmaceutical companyrdquo Journal of Ethnopharmacol-ogy vol 51 no 1ndash3 pp 29ndash38 1996

[95] D E Moerman ldquoAn analysis of the food plants and drug plantsof native North Americardquo Journal of Ethnopharmacology vol52 no 1 pp 1ndash22 1996

[96] K Nakahara S Kawabata H Ono et al ldquoInhibitory effectof oolong tea polyphenols on glucosyltransferases of mutansstreptococcirdquo Applied and Environmental Microbiology vol 59no 4 pp 968ndash973 1993

[97] A Mori C Nishino N Enoki and S Tawata ldquoAntibacterialactivity and mode of action of plant flavonoids against Proteusvulgaris and Staphylococcus aureusrdquo Phytochemistry vol 26 no8 pp 2231ndash2234 1987

[98] K A Ohemeng C F Schwender K P Fu and J F BarrettldquoDNA gyrase inhibitory and antibacterial activity of someflavones(1)rdquo Bioorganic and Medicinal Chemistry Letters vol 3no 2 pp 225ndash230 1993

[99] H Tsuchiya and M Iinuma ldquoReduction of membrane fluidityby antibacterial sophoraflavanone G isolated from Sophoraexiguardquo Phytomedicine vol 7 no 2 pp 161ndash165 2000

[100] H Haraguchi K Tanimoto Y Tamura K Mizutani and TKinoshita ldquoMode of antibacterial action of retrochalcones fromGlycyrrhiza inflatardquo Phytochemistry vol 48 no 1 pp 125ndash1291998

[101] L E Alcaraz S E Blanco O N Puig F Tomas and F HFerretti ldquoAntibacterial activity of flavonoids againstmethicillin-resistant Staphylococcus aureus strainsrdquo Journal of TheoreticalBiology vol 205 no 2 pp 231ndash240 2000

[102] K Osawa H Yasuda T Maruyama H Morita K Takeya andH Itokawa ldquoIsoflavanones from the heartwood of Swartziapolyphylla and their antibacterial activity against cariogenicbacteriardquo Chemical and Pharmaceutical Bulletin vol 40 no 11pp 2970ndash2974 1992

[103] A Maurya P Chauhan A Mishra and A K Pandey ldquoSurfacefunctionalization of TiO2 with plant extracts and their com-bined antimicrobial activities against E faecalis and E ColirdquoJournal of Research Updates in Polymer Science vol 1 pp 43ndash51 2012

[104] A K Mishra B K Singh and A K Pandey ldquoIn vitro-antibacterial activity and phytochemical profiles of Cinnamo-mum tamala (Tejpat) leaf extracts and oilrdquo Reviews in Infectionvol 1 pp 134ndash139 2010

[105] A K Mishra A Mishra A Bhargava and A K PandeyldquoAntimicrobial activity of essential oils from the leaves ofCinnamomum spprdquo National Academy Science Letters vol 31no 11-12 pp 341ndash345 2008

[106] M H Pan C S Lai and C T Ho ldquoAnti-inflammatory activityof natural dietary flavonoidsrdquo Food and Function vol 1 no 1pp 15ndash31 2010

[107] E Middleton and C Kandaswami ldquoEffects of flavonoids onimmune and inflammatory cell functionsrdquo Biochemical Phar-macology vol 43 no 6 pp 1167ndash1179 1992

[108] Y Nishizuka ldquoThe molecular heterogeneity of protein kinase Cand its implications for cellular regulationrdquoNature vol 334 no6184 pp 661ndash665 1988


[109] T Hunter ldquoProtein kinases and phosphatases the yin and yangof protein phosphorylation and signalingrdquo Cell vol 80 no 2pp 225ndash236 1995

[110] M J Tunon M V Garcia-Mediavilla S Sanchez-Camposand J Gonzalez-Gallego ldquoPotential of flavonoids as anti-inflammatory agents modulation of pro-inflammatory geneexpression and signal transduction pathwaysrdquo Current DrugMetabolism vol 10 no 3 pp 256ndash271 2009

[111] J A Manthey ldquoBiological properties of flavonoids pertaining toinflammationrdquoMicrocirculation vol 7 no 1 pp S29ndashS34 2000

[112] J C Cumella H Faden and F Middleton ldquoSelective activityof plant flavonoids on neutrophil chemiluminescence (CL)rdquoJournal of Allergy and Clinical Immunology vol 77 article 1311987

[113] A Beretz and J P Cazenave ldquoThe effect of flavonoids on blood-vessel wall interactionsrdquo in Plant Flavonoids in Biology andMedicine II Biochemical Cellular and Medicinal Properties VCody EMiddleton J B Harborne andA Beretz Eds pp 187ndash200 Alan R Liss New York NY USA 1988

[114] E Corvazier and J Maclouf ldquoInterference of some flavonoidsand non-steroidal anti-inflammatory drugs with oxidativemetabolism of arachidonic acid by human platelets and neu-trophilsrdquo Biochimica et Biophysica Acta vol 835 no 2 pp 315ndash321 1985

[115] C T Ho T Osawa M T Huang and R T Rosen FoodPhytochemicals for Cancer Prevention II Teas Spices and HerbsAmerican Chemical Society Oxford University Press 1994

[116] B Koen V Ruth V Guido and V S Johannes ldquoInductionof cancer cell apoptosis by flavonoids is associated with theirability to inhibit fatty acid synthase activityrdquo Journal of BiologicalChemistry vol 280 no 7 pp 5636ndash5645 2005

[117] G Block B Patterson and A Subar ldquoFruit vegetables andcancer prevention a review of the epidemiological evidencerdquoNutrition and Cancer vol 18 no 1 pp 1ndash29 1992

[118] G G Duthie S J Duthie and J A M Kyle ldquoPlant polyphenolsin cancer and heart disease implications as nutritional antiox-idantsrdquo Nutrition Research Reviews vol 13 no 1 pp 79ndash1062000

[119] W L Davis and S B Matthew ldquoAntioxidants and cancer IIIquercetinrdquo Alternative Medicine Review vol 5 no 3 pp 196ndash208 2000

[120] D R Ferry A Smith and J Malkhandi ldquoPhase I clinical trial ofthe flavonoid quercetin pharmacokinetics and evidence for invivo tyrosine kinase inhibitionrdquo Clinical Cancer Research vol 2no 4 pp 659ndash668 1996

[121] K Brusselmans E de Schrijver W Heyns G Verhoeven andJ V Swinnen ldquoEpigallocatechin-3-gallate is a potent naturalinhibitor of fatty acid synthase in intact cells and selectivelyinduces apoptosis in prostate cancer cellsrdquo International Journalof Cancer vol 106 no 6 pp 856ndash862 2003

[122] J V Swinnen T Roskams S Joniau et al ldquoOverexpressionof fatty acid synthase is an early and common event inthe development of prostate cancerrdquo International Journal ofCancer vol 98 no 1 pp 19ndash22 2002

[123] B M Markaverich R R Roberts M A Alejandro G AJohnson B S Middleditch and J H Clark ldquoBioflavonoidinteraction with rat uterine type II binding sites and cell growthinhibitionrdquo Journal of Steroid Biochemistry vol 30 no 1ndash6 pp71ndash78 1988

[124] R L Singhal Y A Yeh N Prajda E Olah G W Sledgeand G Weber ldquoQuercetin down-regulates signal transduction

in human breast carcinoma cellsrdquo Biochemical and BiophysicalResearch Communications vol 208 no 1 pp 425ndash431 1995

[125] S Barnes ldquoEffect of genistein on in vitro and in vivo models ofcancerrdquo Journal of Nutrition vol 125 no 3 pp 777Sndash783S 1995

[126] C A Lamartiniere J Moore M Holland and S BarnesldquoNeonatal genistein chemoprevents mammary cancerrdquo Pro-ceedings of the Society for Experimental Biology and Medicinevol 208 no 1 pp 120ndash123 1995

[127] W Ren Z Qiao H Wang L Zhu and L Zhang ldquoFlavonoidspromising anticancer agentsrdquo Medicinal Research Reviews vol23 no 4 pp 519ndash534 2003

[128] K K Carroll N Guthrie F V So and A F ChambersldquoAnticancer properties of flavonoids with emphasis on citrusflavonoidsrdquo in Flavonoids in Health and Disease C A Rice-Evans and L Packer Eds pp 437ndash446 Marcel Dekker NewYork NY USA 1998

[129] R Edenharder I P Von and R Rauscher ldquoAntimuta-genic effects of flavonoids chalcones and structurally relatedcompounds on the activity of 2-amino-3-methylimidazo[45-f]quinoline (IQ) and other heterocyclic amine mutagens fromcooked foodrdquo Mutation Research vol 287 no 2 pp 261ndash2741993

[130] L L Thomsen L M Ching L Zhuang J B Gavin and B CBaguley ldquoTumordependent increased plasma nitrate concen-trations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in micerdquo Cancer Research vol 51 no1 pp 77ndash81 1991

[131] R L Chang M T Huang A W Wood et al ldquoEffect of ellagicacid and hydroxylated flavonoids on the tumorigenicity ofbenzo[a]pyrene and (+-)-7 beta 8 alpha-dihydroxy-9 alpha 10alpha-epoxy-78910-tetrahydrobenzo[a]pyrene on mouse skinand in the newborn mouserdquo Carcinogenesis vol 6 no 8 pp1127ndash1133 1985

[132] M H Siess A M Le Bon M C Canivenc-Lavier et alldquoFlavonoids of honey and propolis characterization and effectson hepatic drug-metabolizing enzymes and benzo[a]pyrene-DNA binding in ratsrdquo Journal of Agricultural and Food Chem-istry vol 44 no 8 pp 2297ndash2301 1996

[133] S Kumar G Chashoo A K Saxena and A K PandeyldquoParthenium hysterophorus a probable source of anticancerantioxidant and anti-HIV agentsrdquo BioMed Research Interna-tional vol 2013 Article ID 810734 11 pages 2013

[134] T Sawa M Nakao T Akaike K Ono and H MaedaldquoAlkylperoxyl radical-scavenging activity of various flavonoidsand other phenolic compounds implications for the anti-tumor-promoter effect of vegetablesrdquo Journal of Agriculturaland Food Chemistry vol 47 no 2 pp 397ndash402 1999

[135] B Gerdin and E Srensso ldquoInhibitory effect of the flavonoidon increased microvascular permeability induced by variousagents in rat skinrdquo International Journal of MicrocirculationClinical and Experimental vol 2 no 1 pp 39ndash46 1983


[137] B Q Li T Fu Y Dongyan J A Mikovits F W Ruscettiand J M Wang ldquoFlavonoid baicalin inhibits HIV-1 infectionat the level of viral entryrdquo Biochemical and Biophysical ResearchCommunications vol 276 no 2 pp 534ndash538 2000

[138] JWCritchfield S T Butera andTM Folks ldquoInhibition ofHIVactivation in latently infected cells by flavonoid compoundsrdquoAIDS Research and Human Retroviruses vol 12 no 1 pp 39ndash46 1996


[139] K Zandi B T Teoh S S Sam P F Wong M R Mustafa andS Abubakar ldquoAntiviral activity of four types of bioflavonoidagainst dengue virus type-2rdquoVirology Journal vol 8 article 5602011

[140] B W Shirley ldquoFlavonoid biosynthesis ldquonewrdquo functions for anldquooldrdquo pathwayrdquo Trends in Plant Science vol 1 no 11 pp 377ndash382 1996


[142] G Agati andM Tattini ldquoMultiple functional roles of flavonoidsin photoprotectionrdquo New Phytologist vol 186 no 4 pp 786ndash793 2010

[143] J Zhao and R A Dixon ldquoThe ldquoinsrdquo and ldquooutsrdquo of flavonoidtransportrdquoTrends in Plant Science vol 15 no 2 pp 72ndash80 2010

[144] M R Perez-Gregorio J Regueiro C G Barreiro R R Oteroand J S Gandara ldquoChanges in antioxidant flavonoids duringfreeze-drying of red onions and subsequent storagerdquo FoodControl vol 22 no 7 pp 1108ndash1113 2011

[145] M D Ferdinando C Brunetti A Fini and M TattinildquoFlavonoids as antioxidants in plants under abiotic stressesrdquo inAbiotic Stress Responses in Plants Metabolism Productivity andSustainability P Ahmad andM N V Prasad Eds pp 159ndash179Springer New York NY USA 2012

[146] J H B Hatier and K S Gould ldquoFoliar anthocyanins asmodulators of stress signalsrdquo Journal of Theoretical Biology vol253 no 3 pp 625ndash627 2008

[147] P M Mullineaux and S Karpinski ldquoSignal transduction inresponse to excess light getting out of the chloroplastrdquo CurrentOpinion in Plant Biology vol 5 no 1 pp 43ndash48 2002

[148] M Tattini C Galardi P Pinelli R Massai D Remoriniand G Agati ldquoDifferential accumulation of flavonoids andhydroxycinnamates in leaves of Ligustrum vulgare under excesslight and drought stressrdquoTheNew Phytologist vol 163 no 3 pp547ndash561 2004

[149] A G Erlejman S V Verstraeten C G Fraga and P I OteizaldquoThe interaction of flavonoids withmembranes potential deter-minant of flavonoid antioxidant effectsrdquo Free Radical Researchvol 38 no 12 pp 1311ndash1320 2004

[150] L P Taylor and E Grotewold ldquoFlavonoids as developmentalregulatorsrdquo Current Opinion in Plant Biology vol 8 no 3 pp317ndash323 2005

[151] M A K Jansen ldquoUltraviolet-B radiation effects on plantsinduction of morphogenic responsesrdquo Physiologia Plantarumvol 116 no 3 pp 423ndash429 2002

[152] B H Kuhn M Geisler L Bigler and C Ringli ldquoFlavonolsaccumulate asymmetrically and affect auxin transport in Ara-bidopsirdquo Plant Physiology vol 156 no 2 pp 585ndash595 2011

[153] U Mathesius ldquoFlavonoids induced in cells undergoing noduleorganogenesis in white clover are regulators of auxin break-down by peroxidaserdquo Journal of Experimental Botany vol 52pp 419ndash426 2001

[154] D E Saslowsky U Warek and B S J Winkel ldquoNuclearlocalization of flavonoid enzymes in Arabidopsisrdquo Journal ofBiological Chemistry vol 280 no 25 pp 23735ndash23740 2005

[155] M Naoumkina and R A Dixon ldquoSubcellular localization offlavonoid natural productsrdquo Plant Signaling and Behavior vol3 no 8 pp 573ndash575 2008

[156] Y Wang S Chen and O Yu ldquoMetabolic engineering offlavonoids in plants andmicroorganismsrdquoAppliedMicrobiologyand Biotechnology vol 91 no 4 pp 949ndash956 2011

[157] S R Park J A Yoon J H Paik et al ldquoEngineering ofplant-specific phenylpropanoids biosynthesis in Streptomycesvenezuelaerdquo Journal of Biotechnology vol 141 no 3-4 pp 181ndash188 2009

[158] AWang F Zhang LHuang et al ldquoNewprogress in biocatalysisand biotransformation of flavonoidsrdquo Journal ofMedicinal PlantResearch vol 4 no 10 pp 847ndash856 2010

[159] E I Hwang M Kaneko Y Ohnishi and S HorinouchildquoProduction of plant-specific flavanones by Escherichia colicontaining an artificial gene clusterrdquoApplied and EnvironmentalMicrobiology vol 69 no 5 pp 2699ndash2706 2003

[160] M B Austin and J P Noel ldquoThe chalcone synthase superfamilyof type III polyketide synthasesrdquo Natural Product Reports vol20 no 1 pp 79ndash110 2003

[161] E Leonard and M A G Koffas ldquoEngineering of artificialplant cytochrome P450 enzymes for synthesis of isoflavones byEscherichia colirdquo Applied and Environmental Microbiology vol73 no 22 pp 7246ndash7251 2007

[162] E Leonard Y Yan Z L Fowler et al ldquoStrain improvement ofrecombinant Escherichia coli for efficient production of plantflavonoidsrdquoMolecular Pharmaceutics vol 5 no 2 pp 257ndash2652008

[163] S Horinouchi ldquoCombinatorial biosynthesis of non-bacterialand unnatural flavonoids stilbenoids and curcuminoids bymicroorganismsrdquo Journal of Antibiotics vol 61 no 12 pp 709ndash728 2008

[164] E G W M Schijlen C H R de Vos A J van Tunen and AG Bovy ldquoModification of flavonoid biosynthesis in crop plantsrdquoPhytochemistry vol 65 no 19 pp 2631ndash2648 2004

[165] C N S Santos M Koffas and G Stephanopoulos ldquoOptimiza-tion of a heterologous pathway for the production of flavonoidsfrom glucoserdquoMetabolic Engineering vol 13 no 4 pp 392ndash4002011

[166] K Frank B Jules C Barbara et al ldquoDe novo production of theflavonoid naringenin in engineered Saccharomyces cerevisiaerdquoMicrobial Cell Factories vol 11 article 155 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


A C

BO1

2

3

456

78 1

998400

2998400

3998400

4998400

5998400

6998400

Figure 1 Basic flavonoid structure

2 Chemistry of Flavonoids

Flavonoids are a group of natural compounds with variablephenolic structures and are found in plants In 1930 a newsubstance was isolated from oranges At that time it wasbelieved to be a member of a new class of vitamins and wasdesignated as vitamin P Later on it became clear that thissubstancewas a flavonoid (rutin) and till nowmore than 4000varieties of flavonoids have been identified [13]

Chemically flavonoids are based upon a fifteen-carbonskeleton consisting of two benzene rings (A and B asshown in Figure 1) linked via a heterocyclic pyrane ring(C) They can be divided into a variety of classes such asflavones (eg flavone apigenin and luteolin) flavonols (egquercetin kaempferol myricetin and fisetin) flavanones(eg flavanone hesperetin and naringenin) and othersTheir general structures are shown in Table 1 The variousclasses of flavonoids differ in the level of oxidation andpatternof substitution of the C ring while individual compoundswithin a class differ in the pattern of substitution of the A andB rings [13]

Flavonoids occur as aglycones glycosides and methy-lated derivatives The basic flavonoid structure is aglycone(Figure 1) Six-member ring condensed with the benzenering is either a 120572-pyrone (flavonols and flavanones) or itsdihydroderivative (flavonols and flavanones) The positionof the benzenoid substituent divides the flavonoid classinto flavonoids (2-position) and isoflavonoids (3-position)Flavonols differ from flavanones by hydroxyl group at the 3-position and a C2ndashC3 double bond [40] Flavonoids are oftenhydroxylated in positions 3 5 7 2 31015840 41015840 and 51015840 Methyl ethersand acetyl esters of the alcohol group are known to occur innature When glycosides are formed the glycosidic linkageis normally located in positions 3 or 7 and the carbohydratecan be L-rhamnose D-glucose glucorhamnose galactose orarabinose [41]

21 Spectral Characteristics of Flavonoids Studies onflavonoids by spectroscopy have revealed that most flavonesand flavonols exhibit two major absorption bands Band I(320ndash385 nm) represents the B ring absorption while BandII (250ndash285 nm) corresponds to the A ring absorptionFunctional groups attached to the flavonoid skeleton maycause a shift in absorption such as from 367 nm in kaempferol(35741015840-hydroxyl groups) to 371 nm in quercetin (3573101584041015840-hydroxyl groups) and to 374 nm in myricetin (357310158404101584051015840-hydroxyl groups) [42] The absence of a 3-hydroxyl group in

flavones distinguishes them from flavonols Flavanones havea saturated heterocyclic C ring with no conjugation betweenthe A and B rings as determined by their UV spectralcharacteristics [43] Flavanones exhibit a very strong BandII absorption maximum between 270 and 295 nm namely288 nm (naringenin) and 285 nm (taxifolin) and only ashoulder for Band I at 326 and 327 nm Band II appears asone peak (270 nm) in compounds with a monosubstituted Bring but as two peaks or one peak (258 nm) with a shoulder(272 nm) when a di- tri- or o-substituted B ring is presentAs anthocyanins show distinctive Band I peak in the 450ndash560 nm region due to hydroxyl cinnamoyl system of the Bring and Band II peaks in the 240ndash280 nm region due to thebenzoyl system of the A ring the colour of the anthocyaninsvaries with the number and position of the hydroxyl groups[44]

3 Flavonoid Rich Food and Medicinal Plants

Flavonoids are the most common and widely distributedgroup of plant phenolic compounds occurring virtually inall plant parts particularly the photosynthesising plant cellsThey are a major coloring component of flowering plantsFlavonoids are an integral part of human and animal dietSome food sources containing different classes of flavonoidsare given in Table 2 Being phytochemicals flavonoids cannotbe synthesized by humans and animals [45] Thus flavonoidsfound in animals are of plant origin rather than being biosyn-thesized in situ Flavonols are the most abundant flavonoidsin foods Flavonoids in food are generally responsible forcolour taste prevention of fat oxidation and protection ofvitamins and enzymes [46] Flavonoids found in the highestamounts in the human diet include the soy isoflavonesflavonols and the flavones Although most fruits and somelegumes contain catechins the levels vary from 45 to610mgkg [47] Preparation and processing of food maydecrease flavonoid levels depending on the methods usedFor example in a recent study orange juices were found tocontain 81ndash200mgL soluble flavanones while the contentin the cloud was 206ndash644mgL which suggest that theflavanones are concentrated in the cloud during processingand storage [48] Accurate estimation of the average dietaryintake of flavonoids is difficult because of thewide varieties ofavailable flavonoids and the extensive distribution in variousplants and also the diverse consumption in humans [49]

Recently there has been an upsurge of interest in thetherapeutic potential of medicinal plants which might bedue to their phenolic compounds specifically to flavonoids[50 51] Flavonoids have been consumed by humans sincethe advent of human life on earth that is for about 4million years They have extensive biological properties thatpromote human health and help reduce the risk of diseasesOxidative modification of LDL cholesterol is thought to playa key role during atherosclerosis The isoflavan glabridin amajor polyphenolic compound found in Glycyrrhiza glabra(Fabaceae) inhibits LDL oxidation via a mechanism involv-ing scavenging of free radicals [52] Several epidemiologicstudies have suggested that drinking either green or black




FlavonesO

O

O

O

HO

OH

HOOH

Luteolin

O

O

HO

OH

OH

Apigenin

O

O

HO

OH

Chrysin

FlavonolsO

OOH

O

OOH

HO

OH

OHHO

Quercetin

O

OOH

HO

OH

OH

Kaempferol

O

OOH

HO

OH

Galangin

FlavanonesO

O

O

O

HO

OH

HOO

Hesperetin

CH 3 O

O

HO

OH

OH

Naringenin

FlavanonolO

OOH

O

OOH

HO

OH

OHOH

Taxifolin

Isoflavones

O

O

O

OOH

HO

OH

Genistein

O

OOH

HO

Daidzein

Flavan-3-olsO

OH

O

OH

HO

OH

OHOH

Catechin

O

OH

HO

OH

OH

OH

Epicatechin








Tea [14]














O

O

OO

OH

OH

OH

OH

OH

OH

HO

HO

(a)

O

O

OH

OH

OH

OH

HO

(b)







Colon

Small intestine

Feces

LiverOther tissue

Kidney

Urine


form)





OH

OH

Fl-OH

R∘ RH

O∘

OH

∘F1-O

O∘

OH

R∘ RH OO

(a)

HO

A

O

O

Men+Men+

OH

B3998400

4998400

HO Men+

OH

(b)










































[32 33]



[35]



























8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




FlavonesO

O

O

O

HO

OH

HOOH

Luteolin

O

O

HO

OH

OH

Apigenin

O

O

HO

OH

Chrysin

FlavonolsO

OOH

O

OOH

HO

OH

OHHO

Quercetin

O

OOH

HO

OH

OH

Kaempferol

O

OOH

HO

OH

Galangin

FlavanonesO

O

O

O

HO

OH

HOO

Hesperetin

CH 3 O

O

HO

OH

OH

Naringenin

FlavanonolO

OOH

O

OOH

HO

OH

OHOH

Taxifolin

Isoflavones

O

O

O

OOH

HO

OH

Genistein

O

OOH

HO

Daidzein

Flavan-3-olsO

OH

O

OH

HO

OH

OHOH

Catechin

O

OH

HO

OH

OH

OH

Epicatechin








Tea [14]














O

O

OO

OH

OH

OH

OH

OH

OH

HO

HO

(a)

O

O

OH

OH

OH

OH

HO

(b)







Colon

Small intestine

Feces

LiverOther tissue

Kidney

Urine


form)





OH

OH

Fl-OH

R∘ RH

O∘

OH

∘F1-O

O∘

OH

R∘ RH OO

(a)

HO

A

O

O

Men+Men+

OH

B3998400

4998400

HO Men+

OH

(b)










































[32 33]



[35]



























8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Tea [14]














O

O

OO

OH

OH

OH

OH

OH

OH

HO

HO

(a)

O

O

OH

OH

OH

OH

HO

(b)







Colon

Small intestine

Feces

LiverOther tissue

Kidney

Urine


form)





OH

OH

Fl-OH

R∘ RH

O∘

OH

∘F1-O

O∘

OH

R∘ RH OO

(a)

HO

A

O

O

Men+Men+

OH

B3998400

4998400

HO Men+

OH

(b)










































[32 33]



[35]



























8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


O

O

OO

OH

OH

OH

OH

OH

OH

HO

HO

(a)

O

O

OH

OH

OH

OH

HO

(b)







Colon

Small intestine

Feces

LiverOther tissue

Kidney

Urine


form)





OH

OH

Fl-OH

R∘ RH

O∘

OH

∘F1-O

O∘

OH

R∘ RH OO

(a)

HO

A

O

O

Men+Men+

OH

B3998400

4998400

HO Men+

OH

(b)










































[32 33]



[35]



























8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


OH

OH

Fl-OH

R∘ RH

O∘

OH

∘F1-O

O∘

OH

R∘ RH OO

(a)

HO

A

O

O

Men+Men+

OH

B3998400

4998400

HO Men+

OH

(b)










































[32 33]



[35]



























8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


































[32 33]



[35]



























8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





















8 Conclusion





Acknowledgment


References





















































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

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