Activation/Detoxication. Non-polar (lipophilic) Hydrophobic Lipophobic Hydrophilic (Polar) XENOBIOTIC INTERMEDIATE METABOLITE ELIMINATION WATER-SOLUBLE.

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Presentation transcript:

Activation/Detoxication

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

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

Another example Organophosphate Insecticides: Parathion Malathion

Parathion

Malathion

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

Effect is the outcome of interaction between susceptibility and exposure

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

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

Intestines Hepatic portal vein Liver Vena cavaAorta Lungs

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

Reaction Glucuronidation

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

Enterohepatic recirculation (EHC) Liver Intestine

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

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)

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

Changes in P450 levels with age Rats 2A1 2C6 3A2 M: 2C6, 2C11, 3A2 F: 2A1, 2C6, 2C12

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)

Dose