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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. The main purpose of this pilot study is to identify an optimal concentration of diesel exhaust which can be used to study the risks of cardiac changes in healthy older subjects. Results from this study may increase the understanding of how gaseous and particulate air pollutants (which causes the haze seen in some polluted cities) may adversely affect the functioning of the human cardiovascular and respiratory systems. This pilot research will study the responses to diesel exhaust in healthy older subjects with the specific GSTM1 and GSTP1 genotype. For more information, please visit our web site at www.epastudies.org or call Westat EPA Recruiting at 966-0604. Approved June 08, 2007 by the Committee on the Protection of the Rights of Human Subjects Biomedical Institutional Review Board. IRB # 07-0190 (GCRC #2579). This email is sponsored by: U.S. Environmental Protection Agency Human Studies Division located on the UNC-Chapel Hill campus. This email is sponsored by: U.S. Environmental Protection Agency Human Studies Division This email is sponsored by: CEMALB

  5. Another example Organophosphate Insecticides: • Parathion • Malathion

  6. Parathion

  7. Malathion

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

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

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

  11. 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

  12. Lungs Vena cava Aorta Liver Hepatic portal vein Intestines

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

  14. Reaction Glucuronidation

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

  16. Enterohepatic recirculation(EHC) Liver Intestine

  17. 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

  18. 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)

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

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

  21. 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 ?

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

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