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The Metabolism of XENOBIOTICS Reported by Group III, 1-C2 What are Xenobiotics? •Amay be naturalthat or synthetic foreign to the body. compound is “stranger” • may be harmful or safe EXAMPLES OF CARCINOGENIC XENOBIOTICS • Food components methyl glyoxal (coffee) Xenoaflatoxin • Food contaminants B1 = • Cigarette smoke • Industrial (occupational)dibromoethane • Industrial (effluent) vinyl chloride •Cyanide is one example which is toxic at very low levels Principal Classes of Xenobiotics Drugs Chemical carcinogens PCB’s Insecticides Most synthetic materials There are 200,000 of these How does the body handle them? For convenience, the metabolism of xenobiotics is divided into 2 phases There are approximately 30 different enzymes that catalyze xenobiotic compounds 1. Phase 1 •Most common reaction: hydroxylation 2 phases •Some enzymes: monooxygenases microsomal cytochrome-P450s 2. Phase 2 •Most common reactions: conjugation methylation •Enzymes: transferases Phase 1 Mainly hydroxylation reactions Enzyme: Microsomal Cytochromes P450s Purpose: 1. Make the toxin more water-soluble 2. Sometimes deactivates the toxin Phase 1: Microsomal cytochrome P450s Large number of isoforms All contains heme Has a special nomenclature: CYP Family 2 CYPs with >40% similarity Subfamily C CYPs with >55% similarity Specific 9 # CYPs with >100% (exact) similarity Phase 1: = A cytochrome that metabolizes warfarin CYP 2 C 9 Phase 1: Microsomal cytochrome P450s Large number of isoforms All contains heme Has a special nomenclature: Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Inducible (CYP2C9) Some exhibit polymorphism Rarely, some contribute to cancer formation Phase 1: Inducible (CYP2C9) Microsomal cytochrome P450s Large number of isoforms All contains heme Has a special nomenclature: Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Inducible (CYP2C9) Some exhibit polymorphism Rarely, some contribute to cancer formation Phase 1: Inducible (CYP2C9) Q: If you give phenobarbital to a patient who is dependent on warfarin, you have to adjust (higher) the dose of the latter or risk bleeding. Why? A: CYP2C9 , which metabolizes (inactivates) warfarin is induced by phenobarbital. Q: Drinking along with smoking increases risk of cancer than smoking all by itself. Why? A: CYP2E1, which is induced by ethanol (in liquor) is one of the cytochromes that contribute to the activation of procarcinogens found in tobacco smoke. Phase 1: Microsomal cytochrome P450s Large number of isoforms All contains heme Has a special nomenclature: Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Inducible (CYP2C9) Some exhibit polymorphism Rarely, some contribute to cancer formation Phase 1: CYP1A1, CYP2E1: An isoform of cytochrome P450 metabolize inactive PAHs (polycyclic aromatic hydrocarbons) into active carcinogens PAHs are abundant in cigarette smoke Smokers have increased levels of CYP1A1 in their cells than non-smokers. CYP2E1 is induced by ethanol. Rarely, some contribute to cancer formation Phase 1: Microsomal cytochrome P450s Large number of isoforms All contains heme Has a special nomenclature: Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Inducible (CYP2C9) Some exhibit polymorphism Rarely, some contribute to cancer formation Phase 1: CYP2D6 CYP2D6 is involved in the metabolism of debrisoquin (antihypertensive drug) and sparteine (antiarrhythmic and oxytocic drug) Polymorphisms (many different forms of CYP2D6 in the same medium) contribute to the lower the overall activity of the enzyme. This is because some of the “variant forms” have low catalytic activity which pulls the overall activity down. The poor catalysis of debrisoquin and sparteine allows them to stay and accumulate in the body and cause toxicity. Some exhibit polymorphism Polymorphisms and differences between enzyme structure between individuals is genetic Phase 2 Conjugation reactions Enzyme: Transferases Purpose: Make the toxin further watersoluble for excretion Xenobiotic Processing of Xenobiotics Out Reactive Metabolite Nontoxic Metabolite Cell injury Hapten Mutation Antibody reaction Cancer Phase 2: Conjugation Rxn Glucoronidation (most frequently used by the body) Enzyme Glucoronosyltransferases Donor Examples of Xenobiotic Targets UDPglucoronic acid 2-acetylaminoflourene, benzoic acid, aniline, phenols Sulfation --- PAPS (active sulfate) Alcohols, arylamines, phenols Conj. w/ Glutathione --- G-SH form Electrophilic xenobiotics (R) R + G-SH R-S-G Methylation Acetylation Methyltransferases SAM Acetyl-CoA isoniazid