1. Activation/Detoxication

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

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

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 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 Location, location, location

12. Intestines Hepatic portal vein Liver Vena cavaAorta Lungs

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

14. Reaction Glucuronidation

15. Reaction OH o o OH HO OH COOH De-glucuronidation  -glucuronidase AglyconeConjugate

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 age Rats 2A1 2C6 3A2 M: 2C6, 2C11, 3A2 F: 2A1, 2C6, 2C12

21. Cross-species extrapolation What factors are similar ? What factors are different ? The basic problem: data determined in experimental animals Information needed about target species (usually humans)

22. Dose