XENOBIOTICS The Metabolism of Reported by Group III, 1-C2

What are Xenobiotics? A compound that is to the body. Xeno = foreign “stranger” may be natural or synthetic may be harmful or safe EXAMPLES OF CARCINOGENIC XENOBIOTICS Food components methyl glyoxal (coffee) Food contaminants aflatoxin 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’sInsecticides There are 200,000 of these Most synthetic materials

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 2 phases

1.Phase 1 : : Most common reaction: hydroxylation Some enzymes: monooxygenases microsomal cytochrome-P450s Most common reactions: conjugation methylation Enzymes: transferases 2.Phase 2

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 Large number of isoforms All contains heme All contains heme Has a special nomenclature: Has a special nomenclature: CYP FamilySubfamilySpecific # CYPs with >40% similarity CYPs with >55% similarity CYPs with >100% (exact) similarity 2C9

Phase 1: CYP2C9 = A cytochrome that metabolizes warfarin

Phase 1: Microsomal cytochrome P450s Large number of isoforms Large number of isoforms All contains heme All contains heme Has a special nomenclature: Has a special nomenclature: Plenty in liver (in the SER) Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Has lipid components (primarily lecithin) Inducible (CYP2C9) Inducible (CYP2C9) Some exhibit polymorphism Some exhibit polymorphism Rarely, some contribute to cancer formation Rarely, some contribute to cancer formation

Phase 1: Microsomal cytochrome P450s Large number of isoforms Large number of isoforms All contains heme All contains heme Has a special nomenclature: Has a special nomenclature: Plenty in liver (in the SER) Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Has lipid components (primarily lecithin) Inducible (CYP2C9) Inducible (CYP2C9) Some exhibit polymorphism Some exhibit polymorphism Rarely, some contribute to cancer formation Rarely, some contribute to cancer formation Inducible (CYP2C9) Inducible (CYP2C9) Some exhibit polymorphism Some exhibit polymorphism Rarely, some contribute to cancer formation Rarely, some contribute to cancer formation Inducible (CYP2C9) Inducible (CYP2C9)

Phase 1: Inducible (CYP2C9) 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 Large number of isoforms All contains heme All contains heme Has a special nomenclature: Has a special nomenclature: Plenty in liver (in the SER) Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Has lipid components (primarily lecithin) Inducible (CYP2C9) Inducible (CYP2C9) Some exhibit polymorphism Some exhibit polymorphism Rarely, some contribute to cancer formation

Phase 1: Rarely, some contribute to cancer formation Rarely, some contribute to cancer formation  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. CYP1A1, CYP2E1:

Phase 1: Microsomal cytochrome P450s Large number of isoforms Large number of isoforms All contains heme All contains heme Has a special nomenclature: Has a special nomenclature: Plenty in liver (in the SER) Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450 Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin) Has lipid components (primarily lecithin) Inducible (CYP2C9) Inducible (CYP2C9) Some exhibit polymorphism Rarely, some contribute to cancer formation

Phase 1: Some exhibit polymorphism Some exhibit polymorphism 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.  Polymorphisms and differences between enzyme structure between individuals is genetic

Phase 2 Conjugation reactions Enzyme: Transferases Purpose: Make the toxin further water- soluble for excretion

Processing of Xenobiotics Xenobiotic Reactive Metabolite Nontoxic Metabolite Cell injury Hapten Mutation Antibody reaction Cancer Out

Phase 2: Conjugation Rxn EnzymeDonor Examples of Xenobiotic Targets Glucoronidation (most frequently used by the body) Glucoronosyl-transferases UDP- glucoronic 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 R + G-SH  R-S-G Methylation Methyl- transferases SAM AcetylationAcetyl-CoAisoniazid