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Activation/Detoxication

Activation/Detoxication. Non-polar (lipophilic). Hydrophobic. XENOBIOTIC. Phase I Metabolism. Oxidation. Can accumulate in tissues. Solubility in lipids. INTERMEDIATE METABOLITE. Phase II Metabolism. Conjugation. Solubility in water. May be reactive/toxic. WATER-SOLUBLE METABOLITE.

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Activation/Detoxication

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  1. Activation/Detoxication

  2. Non-polar (lipophilic) Hydrophobic XENOBIOTIC Phase I Metabolism Oxidation Can accumulate in tissues Solubility in lipids INTERMEDIATE METABOLITE Phase II Metabolism Conjugation Solubility in water May be reactive/toxic WATER-SOLUBLE METABOLITE Lipophobic Hydrophilic (Polar) ELIMINATION

  3. METABOLIC SCHEME OF BENZO[a]PYRENE (BP, B[a]P) proximate metabolites ultimate active metabolite BPDE 7,8-Quinone 7,8-catechol

  4. Another example Organophosphate Insecticides: • Parathion • Malathion

  5. Parathion

  6. Malathion

  7. Hydrolysis enzymes • Serum cholinesterase BChE • Serum paraoxonase PON1 • Polymorphisms in PON1 – differential sensitivity Heart disease Atherosclerosis Gulf War Syndrome

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

  9. Target organs • What makes a particular organ a target for toxicity / infection ? • What makes a particular organ or species susceptible ?

  10. Portal of entry to Blood to Target Organ Location, location, location e.g. Intestine to hepatic portal vein to liver to vena cava to heart to lungs back to heart to aorta to rest of body

  11. Lungs Vena cava Aorta Liver Hepatic portal vein Intestines

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

  13. Reaction Glucuronidation

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

  15. Enterohepatic recirculation(EHC) Liver Intestine

  16. Presence/absence of receptors • Estrogen receptors, Ah receptor • Presence/absence of transporters/carriers • Resistance to chemotherapy • Presence of repair mechanisms • DNA repair • Balance of metabolic activation/detoxication

  17. 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)

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

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

  20. 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 ?

  21. Dose

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