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“Other” detoxication mechanisms

“Other” detoxication mechanisms. P-glycoprotein: ATP-dependent carrier that removes molecules from cells Multidrug resistance associated protein MDR Multispecific organic anion transporter MOAT. Major reactive species. Electrophiles Epoxides Carbonium ions Arylnitrenium ions

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“Other” detoxication mechanisms

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  1. “Other” detoxication mechanisms • P-glycoprotein: ATP-dependent carrier that removes molecules from cells • Multidrug resistance associated protein MDR • Multispecific organic anion transporter MOAT

  2. Major reactive species Electrophiles Epoxides Carbonium ions Arylnitrenium ions Reactive Oxygen Species

  3. Epoxide hydrolase • Several isoforms • Inducible • Mainly in endoplasmic reticulum, also in cytosol and in nuclear envelope • Catalyse trans addition of water to epoxides

  4. Epoxide hydrolaseReaction

  5. trans-dihydrodiols • Detoxication products from epoxides (PAH) • Targets for Phase II metabolism (glucuronidation, sulfation) • Oxidized by dihydrodiol dehydrogenases to quinones • On terminal rings, oxidized to diol-epoxides

  6. Dioxygenases Microbial enzymes Form cis-dihydrodiols

  7. Complete mineralization • cis-dihydrodiol to catechol • ring-cleavage, b-oxidation, formation of CO2

  8. Reactive Oxygen Species (ROS) • Peroxides • Hydrogen peroxide HOOH • Peroxynitrite OONO- • Lipid hydroperoxide LOOH • Free radicals • Superoxide anion O2•- • Hydroxyl radical HO• • Nitric oxide NO•

  9. NADH NADPH Catalytic cycle of cytochrome P450 ROH H+ Fe3+ + RH HO22- Fe3+-RH H2O Fe3+-RH + e- from NADPH-cytC reductase H2O2 H+ HO2- [Fe2+-RH] Fe2+-RH O2 [Fe2+-RH] +O2 O2-. H+ + e-

  10. Non-enzymic reaction with anti-oxidants • Ascorbic acid (Vitamin C) • alpha-Tocopherol (Vitamin E) • Glutathione

  11. Superoxide dismutase Converts superoxide radicals to hydrogen peroxide O2•- +O2•- + 2H+ O2 + H2O2

  12. Peroxidases Couple reduction of hydrogen peroxide (or other peroxide) to oxidation of another substrate (co-oxidation) ROOH + R’H ROH + R’OH

  13. Peroxidases • Catalase • Prostaglandin synthetase • Myeloperoxidase • Lactoperoxidase • Glutathione peroxidase

  14. Glutathione peroxidase GSH + GSH GSSG HOOH HOH + HOH

  15. Gut flora • Reductions • nitro to amine • Hydrolyses • Cleavage of glucuronides

  16. Reaction Glucuronidation

  17. C O O H O H o o H O O H O H Reaction De-glucuronidation b-glucuronidase Aglycone Conjugate

  18. Enterohepatic recirculation(EHC) Liver Intestine

  19. Gastrointestinal tract

  20. Metabolic Activation/Metabolic Detoxication • “Metabolism is a double-edged sword” • Generation of (re)active intermediates • Detoxication of (re)active intermediates Pharmacologically active Chemically reactive

  21. Major reactive species Electrophiles Epoxides (Epoxide hydrolase Glutathione S-transferase) Carbonium ions Arylnitrenium ions Reactive Oxygen Species

  22. Factors affecting xenobiotic metabolism • Intrinsic • Species, strain, gender, age, genotype • Physiological status • Temperature, time of day, season, • Health status, disease, stress • Diet, nutritional status • Related to exposure • Route of administration, frequency and size of dose, co-exposures (induction, inhibition

  23. Changes in P450 levels with ageRats M: 2C6, 2C11, 3A2 F: 2A1, 2C6, 2C12 2A1 2C6 3A2

  24. Data determined in experimental animals (often rodents) Information needed about target species (usually humans)

  25. Cross-species extrapolation The basic problem: data determined in experimental animals Information needed about target species (usually humans) • What factors are similar ? • What factors are different ? Differences between individuals (interindividual variation)

  26. Genetic polymorphisms • CYP2D6 Debrisoquine hydroxylation (poor and extensive metabolizers) • Acetylation (fast and slow acetylators) • GSTM null genotype

  27. Effect is the outcome of interaction between susceptibility and exposure

  28. What makes a particular organ or species susceptible ?

  29. Genetic Toxicology Reading material: Casarett and Doull Chapter 9, Timbrell, Chapter 6, pp. 259-279

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