PREDICTION OF METABOLIC PATHWAYS FOR TOXIC CHEMICALS

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A major obstacle confronting toxicologists is the quantitative assessment of risk of toxicity by environmental chemicals, food additives and drugs in one species (e.g., humans) based on toxicological studies in another species. Errors in extrapolation frequently arise from species differences in the metabolism of the toxicant. Nevertheless, recent progress in studies of the mammalian mixed-function oxidase (MFO) enzyme system, the primary toxicant metabolizing enzymes, suggest certain interspecies commonalities in catalytic function. This study will employ regioselectively metabolized MFO substrates to test the hypothesis that quantitative knowledge of the ability of other chemicals to inhibit the metabolism of the test substrates may be used to predict the metabolic fate of a previously untested chemical. Warfarin enantiomers and ethylmorphine will be used as test substrates with hepatic microsomal MFO enzymes obtained from rats and mice. Selective induction and destruction methods will be used to segregate regioselectively distinct MFO enzymes. Rigid analogs of warfarin will be tested as MFO enzyme inhibitors. A quantitative structure-activity relationship (QSAR) model relating inhibitory power to tautomeric form, stereoisomer, lipophilicity and electronic properties will be developed and examined for interspecies differences. The QSAR model will be used to predict the inhibitory ability of another analog, whose metabolic fate will then be determined and related to its inhibitory power. The method can potentially be extended to other untested chemicals as a means of improving toxicological risk assessment.