11/06/08 Discussion - ALL

SECTIONS MEET IN ROOM 107

Hints for making a clear group presentation

11/11/08 Peterson Prions and protein folding

11/13/08 Discussion Work in groups on your group presentations

11/18/08 Bryk HIV/AIDS 11/20/08 Group presentations -

meet in your discussion room

Student presentations

11/25/08 Group presentations - meet in your discussion room

Student presentations

11/27/08 Thanksgiving No class 12/02/08 Group presentations -

meet in your discussion room

Student presentations

12/05/08 Final Exam 3-5 PM Room 107

Final exam

Drug Metabolism or

What’s wrong with more grapefruit juice?

Grapefruit and drugs a potent mix

McGill University Health Centre Journal

Grapefruits are chalk full of vitamin C, potassium and natural fiber. So they have to be good for you, right? Well, not necessarily.

Taking a swallow of grapefruit juice to down your prescription medication could play havoc with the digestion of certain drugs, increasing the amount of medication released into the bloodstream, which could lead to harmful levels or drug toxicity.

To complicate matters, if you have always enjoyed a glass of grapefruit juice, stopping this habit could cause the opposite effect, your body will absorb too little medication.

Drugs that interact with grapefruit juice.

Anxiety: Xanax, Buspar, Versed, Halcion

Depression: Luvox, Zoloft

Allergies: Allegra

Abnormal heart rhythm: Cordarone, quinidine

Heart disease/stroke/blood clots: Coumadin

Epilepsy: Tegretol

Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine

Cough: Dextromethorphan

HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase

Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan

Asthma/Emphysema: Theophylline

High cholesterol: Lipitor, Lescol, Mevacor, Zocor

Pain: Alfenta, Duragesic, Actiq, Sufenta

Furocoumarins in grapefruit juice inhibit certain forms of cytochrome P450

Cytochrome P450

Enzyme found mostly in liver

-steroid hormone biosynthesis from cholesterol

-metabolism of xenobiotics-compounds which are not normally found in the body

-Drugs

-Compounds in food produced by cooking (polyaromatic hydrocarbons, also in tobacco smoke) or microorganisms

Cytochrome P450 has a wide range of roles

-typically organic molecules which are poorly soluble in water

The OH added by P450 can then be used to attach sulfate (SO42-) or a sugar.

The modified drug can be more readily removed by the kidney.

Cytochrome P450 aids in the metabolism of xenobiotics by adding OH to increase the water solubility of the compound

O2 + substrate + 2 electrons

HO-substrate + H2O

Because this enzyme catalyzes the addition of one oxygen atom, it is termed a monooxygenase.

N

NN

N

Fe

Heme

The heme group is a cofactor which contains iron.

Different forms of heme are found in hemoglobins and proteins known as cytochromes.

The iron in a heme can bind oxygen and transfer electrons.

Cytochrome P450 contains heme.

Cytochrome P450’s are integral membrane proteins found in the endoplasmic reticulum-membrane network in cells

Cytochrome P450

http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html

Cytochrome P450

At least 57 different isozymes in humans, over 7700 forms in Nature

isozyme-catalytically and structurally similar but geneticallydistinct enzymes-different genes and amino acid sequences

Different isozymes have different substrate specificities

Individuals have several alleles for P450’s and differ in which isozymes they have

A subset of cytochrome P450’s can be induced, so that more is expressed upon exposure to a compound.

Because of the number of different isozymes and their different substrates and inhibitors, the metabolism of a drug can be altered if an individual takes a second drug.

Since individuals have different combinations of P450’s, they differ in their response to specific drugs

1A2 2B6 2C8 2C19 2C9 2D6 2E1 3A4,5,7

amitriptylinecaffeineclomipramineclozapinecyclobenzaprineestradiolfluvoxaminehaloperidolimipramine N-DeMemexilletinenaproxenolanzapineondansetronphenacetinacetaminophenpropranololriluzoleropivacainetacrinetheophyllinetizanidineverapamil

bupropioncyclophosphamideefavirenzifosfamidemethadone

paclitaxeltorsemideamodiaquinecerivastatinrepaglinide

Proton PumpInhibitors:lansoprazoleomeprazolepantoprazolerabeprazole

Anti-epileptics:diazepamphenytoin(O)S-mephenytoinphenobarbitone

amitriptylinecarisoprodolcitalopramchloramphenicolclomipraminecyclophosphamidehexobarbitalimipramineindomethacinR-mephobarbital

ibuprofenmeloxicamS-naproxenpiroxicamsuprofen

OralHypoglycemicAgents:tolbutamideglipizide

Angiotensin IIBlockers:losartanirbesartan

Sulfonylureas:glyburide/glibenclamide

glimepiridetolbutamide

Beta Blockers:

amitriptylineclomipraminedesipramineimipramineparoxetine

haloperidol

alprenololamphetaminearipiprazoleatomoxetinebufuralolchlorpheniraminechlorpromazinecodeine

fluvoxaminelidocainemetoclopramidemethoxyamphetamine

Anesthetics:enfluranehalothaneisofluranemethoxyfluranesevoflurane

erythromycintelithromycin

Benzodiazepines:

cyclosporinetacrolimus (FK506)

HIV Antivirals

Antihistamines:astemizolechlorpheniramineterfenadine

Calcium ChannelBlockers

HMG CoAReductaseInhibitors:atorvastatincerivastatin

Some substrates of cytochrome P450 isozymes

1A2 2B6 2C8 2C19 2C9 2D6 2E1 3A4,5,7

fluvoxamineciprofloxacin

cimetidine

amiodaronefluoroquinolonesfurafyllineinterferonmethoxsalenmibefradil

thiotepaticlopidine

gemfibrozil

trimethoprim

glitazonesmontelukastquercetin

lansoprazoleomeprazole2pantoprazolerabeprazole

chloramphenicolcimetidinefelbamatefluoxetinefluvoxamineindomethacinketoconazolemodafiniloxcarbazepineprobenicidticlopidinetopiramate

fluconazole

amiodarone

fenofibratefluvastatinfluvoxamineisoniazidlovastatinphenylbutazoneprobenicidsertralinesulfamethoxazolesulfaphenazoleteniposidevoriconazolezafirlukast

bupropionfluoxetineparoxetinequinidine

duloxetineterbinafine

amiodaronecimetidinesertraline

celecoxibchlorpheniraminechlorpromazinecitalopramclemastineclomipraminecocainediphenhydraminedoxepindoxorubicinescitalopramhalofantrinehydroxyzinelevomepromazinemethadonemetoclopramidemibefradil

diethyl-dithiocarbamate

HIV Antivirals:indinavirnelfinavirritonavir

clarithromycinitraconazoleketoconazolenefazodonesaquinavirtelithromycin

aprepitanterythromycinfluconazolegrapefruit juiceverapamildiltiazem

cimetidine

amiodaronechloramphenicoldelaviridine

diethyl-dithiocarbamatefluvoxaminegestodene

Some inhibitors of cytochrome P450 isozymes

1A2chromosome 15

2B6chromosome 6

2C8chromosome 10

2C19chromosome 10

2C9chromosome10

2D6chromosome 22

2E1chromosome10

3A4,5,7chromosome 7

broccolibrussel sproutschar-grilled meatinsulinmethylcholanthrenemodafinilnafcillinbeta-naphthoflavone1omeprazoletobacco

phenobarbitalrifampin

rifampin carbamazepinenorethindroneNOT pentobarbitalprednisonerifampin

rifampinsecobarbital

dexamethasonerifampin

thanolisoniazid

HIV Antivirals:efavirenznevirapine

barbituratescarbamazepineefavirenzglucocorticoidsmodafinilnevirapineoxcarbazepinephenobarbitalphenytoinpioglitazonerifabutinrifampinSt. John's worttroglitazone

Some inducers of cytochrome P450 isozymes

The reaction of cytochrome P450 can also produce a toxic compound:

HNC

CH3

O

Acetaminophen

OH

At normal doses, sulfate or a sugar is attached to OH and the drug is easily removed by the kidney.

At high doses, this pathway cannot keep up and a liver P450 converts acetaminophen to a toxic metabolite which causes liver damage.

Metabolism of acetaminophen (Tylenol)

Metabolism of neurotransmitters-monoamine oxidase

Several important neurotransmitters are amines.

NH3

HO

HO

dopamine

NH3

HO

HO

norepinephrine

NH2

HO

HO

epinephrine

OH

CH3

NH3NH3

NH

HO

serotonin

These are released into the blood where they bind to receptors on the surface of cells.

To ensure that the action of amine neurotransmitters is short, they are destroyed by the enzyme monoamine oxidase.

Monoamines also come from the diet

NH3

HO

tyramine

Tyramine is formed from tyrosine. If blood levels rise they disrupt catecholamine metabolism, leading to possibly fatal hypertension. Monoamine oxidase prevents this.

Foods containing high levels of tyramine:

smoked, aged, or pickled meat or fish; sauerkrautaged cheeses (e.g., swiss, cheddar, blue, boursault, camembert, emmenthaler, stilton);yeast extractsfava beansbeef or chicken liveraged sausages (e.g., bologna, pepperoni, salami, summer sausage)game meats (e.g., venison, rabbit)red wines (e.g., chianti, sherry).

Monoamine oxidase

An integral membrane protein in liver mitochondria.

Oxidizes amines to aldehydes:

NH3

HO

HO O2

OHO

HO

+ NH4

Monoamine oxidase contains FAD as a cofactor

NNH

N

O

O

R'

N

Flavin Adenosine Dinucleotide

Synthesized from the vitamin riboflavin

Used in electron transfer reactions

Monoamine oxidase contains FAD as a cofactor

Monoamine oxidase (MAO) inhibitors are used as antidepressants and to treat eating disorders.

They keep serotonin levels up. Serotonin controls mood.

MAO inhibitors can cause overdoses:No longer break down tyramine from diet.High levels of tryptophan in diet can result in serotonin levels becoming too high.Will prevent metabolism of drugs that are amines. As a result MAO inhibitors can result in serious side effects when used with other drugs.

MAO inhibitors have been replaced with drugs which prevent the binding of serotonin to cells, such as Prozac. These do not affect the metabolism of other amines, so that there are far fewer side effects.

Monoamine oxidase inhibitors