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CYTOCHROME P450 ENZYMES

Presented By Deshmukh Md Faizan M. Pharm (1st Sem) DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, R.C.PATEL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH, SHIRPUR

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CONTENTS… Introduction of Cytochrome P450. Location. Components. Classification And Nomenclature of Cytochrome

P450. Catalytic Cycle of Cytochrome P450. Isoforms of Cytochrome P450. Induction And Inhibition of P450.

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INTRODUCTION... Humans constantly exposed to xenobiotics(usually non

polar) that can cause harmful effect if not eliminated. Biotransformation convert non polar compounds

to polar and helps in their elimination. Biotransformation occurs in 2 phases(phase1

&phase 2). Cytochrome p-450 is a superfamily of enzymes that

catalyse most of the oxidation reactions of phase 1. Require both molecular oxygen and NADPH to effect

reaction. Also called mixed function oxidases and mono-oxygenases.

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LOCATION… Located in endoplasmic reticulum of hepatic cells and

throughout of the body.

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COMPONENTS… Composed of an electron transfer chain consisting of 3

components. 1. heme protein. 2. flavoprotein. 3. phosphatidylcholine. Reaction involving the substrate RH which yields the

product ROH, is given by the following equation:

R-H + O2 + NADPH + H+ → R-OH + H2O + NADP+

Where NADPH=Nicotinamide adenosine dinucleotide phosphate.

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NOMENCLATURE AND CLASSIFICATION… Membrane-bound within a cell (cyto) + heme

pigment (chrome and P) + absorbs light at 450 nm (450) when exposed to CO.

Classified according to their amino acid sequence:

1. Families- proteins with 40% amino acid seq e.g: CYP2, CYP3 2. Subfamilies-member of family have 55%

AAS e.g:CYP2D, CYP3A 3. Individual genes-denoted by arabic

numerical e.g:CYP2D6, CYP3A4

CYP1A2 family subfamily individual member of

that subfamily

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CATALYTIC CYCLE OF CYTOCHROME P450…

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CYTOCHROME P450 ISOFORMS… Isoforms mean same enzyme that belong to

cyp450 enzyme and which having ability to metabolized drug.

There are several isoforms of enzyme which is given below:-

1. CYP1A2 2. CYP2C9 3. CYP2C19 4. CYP2D6 5. CYP2E1 etc.

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1) CYP1A2… Metabolize the chemical and environmental chemicals. 13% total hepatic content of isoenzyme. Drug substrate E.g- caffein, theophylline, propanolol. Drug inhibitor E.g- ciprofloxacin, cimetidine, erythromycin. Drug inducer E.g- hydrocarbon, phenobarbital, rifampicin.

2) CYP2C9… Responsible for metabolism of ibuprofen,

tolbutamide, torsemide. Warfarin is mainly metabolized by this isoforms.

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Inhibitor of warfarin E.g- fluconazole, metronidazole, amiodarone.

3) CYP2C19... Responsible for metabolism of diazepam, omeprazole,

lansoprazole. Poor metabolizers.

4) CYP2D6... Enzyme not inducible by drug. Most drug use in clinical evaluation metabolized by

this isoforms.

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5) CYP2E1... 7% total CYP content in liver. Sevoflurane, isoflurane metabolized by this enzyme. Enzyme responsible for metabolism of paracetamol and

ethanol.

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Isoenzyme

Substrate Inhibitor Inducers

CYP1A2 TheophyllineCaffein

Propanolol etc.

CimetidineCiprofloxacinErythromycin

etc.

HydrocarbonOmeprazole

Phenobarbital etc.

CYP2C9 IbuprofenTolbutamide

Torsemide etc.

FluconazoleAmiodarone

etc.

PhenobarbitalPhenytoin

Rifampicin etc.

CYP2C19 OmeprazoleDaizepam

Lansoprazole etc.

OmeprazoleCimetidineFluconazole

etc.

CarbamazepineRifampicin

Phenobarbitone etc.

CYP2D6 Amitriptyline Codeine

Oxycodone etc.

Haloperidol Indinavir

Quinidine etc.

RifampicinDexamethason

.CYP2E1 Paracetamole

EthanolHalothane etc.

Disulfiram Ethanol and isoniazid

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INDUCTION AND INHIBITION OF CYP450... Induction of drug metabolism can lead to unexpected

drops in drug concentration or the build-up of metabolites. The reverse can occur when there is inhibition of drug metabolism.

The major organ involved in metabolism is liver and the major enzyme system involved in drug metabolism is CYP 450, the well-known family of oxidative hemo-proteins. Induction CYP 450 enzymes at the liver is responsible for induction of metabolism of many drugs.

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INDUCTION OF CYP450... Induction means ability of drug to increase the synthesis of

CYP450 enzymes is called as induction. Most enzyme inducers have following properties 1. They are lipophilic compound. 2. They have long elimination half life. 3. They are substrate for inducted enzyme system.

Mechanisms involved in enzyme induction are 1.Increase in both liver size and liver blood flow. 2.Increase stability of enzymes, synthesis of CYP450. 3.Decrease degradation of CYP450.

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TABLE:- INDUCERS OF DRUG METABOLISING ENZYME SYSTEM AND

DRUGS COMMONLY AFFECTED BY THEM

Inducers Drugs with enchanced Metabolism

Barbiturates Coumarins, phenytoin, testosterones etc.

Alcohol Pentobarbital, Coumarins, phenytoin.

Phenytoin Tolbutamide, cortisol etc.Rifampicin Rifampicin, tolbutamide etc.

Cigarette Smoke Nicotine and amino azo dyes.

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INHIBITION OF CYP450... Decrease in the drug metabolism ability of enzyme by

drug is called enzyme inhibition. inhibition of CYP enzymes can be classified 1.Reversible inhibition. 2.Irreversible inhibition.1. Reversible inhibition... Direct competition for binding site between substrate

and inhibitor. determination of potency of inhibitor. for example:- cimetidine H2 receptor antagonist.

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2. Irreversible inhibition... occur by reactive metabolites generation. first type of irreversible inhibition involves the

formation of metabolic intermediate complexes. inhibition of CYP3A by erythromycin. Transformation reactions such as N-hydroxylation, N-

demethylation, N-oxidation catalyzed by CYP3A.

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TABLE:-ENZYME INHIBITOR AND DRUGS AFFECTED BY THEM

Inhibitors Drugs with Decreased metabolism

MAO inhibitors Barbiturates, TyramineCoumarins PhenytoinAllopurinol 6-Mercatopurine

PAS Phenytoin, Hexobarbital

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REFERENCES...1) Wilson and Gisvolds Textbook of Organic medicinal

and pharmaceutical chemistry, Ninth edition,Page no.48 - 49 &117.

2) William O. Foye Principle of medicinal chemistry,3rd edition, varghese publishing house, Page no.84-85.

3) Bramhankar, D.M. and Sunil B Jaiswal. 2001 Biopharmaceutics and Pharmacokinetics A Treatise, 2nd ed.,Vallabh Prakashan. New Delhi, CT ISBN 978-81-85731=47-6: Page no.181-184.

4) Bhupinder singh kalra, Cytochrome P450 enzyme isoforms and their therapeutic implication: an update, Indian J Med Sci, vol. 61, no. 1, Feb 2007.

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Thank You