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XENOBIOTICS

The Metabolism of. XENOBIOTICS. Reported by Group III, 1-C2. What are Xenobiotics?.     • may be natural or synthetic     • may be harmful or safe

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XENOBIOTICS

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

  2. What are Xenobiotics? •     • 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 foreign • A compound that is to the body. “stranger” Xeno =

  3. Principal Classes of Xenobiotics • Drugs • Chemical carcinogens • PCB’s • Insecticides Most synthetic materials There are 200,000 of these

  4. 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

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

  6. Phase 1 Mainly hydroxylation reactions Enzyme: Microsomal Cytochromes P450s Purpose: 1. Make the toxin more water-soluble 2. Sometimes deactivates the toxin

  7. Phase 1: • Microsomal cytochrome P450s • Large number of isoforms • All contains heme • Has a special nomenclature: CYP 2 C 9 Family Subfamily Specific # CYPs with >40% similarity CYPs with >55% similarity CYPs with >100% (exact) similarity

  8. Phase 1: = A cytochrome that metabolizes warfarin CYP 2 C 9

  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

  10. 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 • Inducible (CYP2C9) • Some exhibit polymorphism • Rarely, some contribute to cancer formation

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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. • Polymorphisms and differences between enzyme structure between individuals is genetic • Some exhibit polymorphism

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

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

  18. Phase 2:

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