1 / 29

“Other” detoxication mechanisms

This article explores the intricate mechanisms of detoxification within biological systems, focusing on key transport proteins like P-glycoprotein and Multidrug Resistance-associated Protein (MDR). It delves into the enzymatic breakdown of reactive intermediates, including electrophiles and reactive oxygen species (ROS), highlighting the roles of epoxide hydrolases and cytochrome P450 in detoxification pathways. The impact of various factors such as genetics, health status, and dietary influences on xenobiotic metabolism is examined, offering insights into individual variability in detoxification capabilities.

natala
Télécharger la présentation

“Other” detoxication mechanisms

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related