ENVIRONMENTAL TOXINS--PREDICTION OF FETAL METABOLISM

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Prediction of fetal/embryonic metabolism is an important consideration in determining the risk associated with exposure of the fetus/embryo to potentially toxic compounds. The objective of this proposal is to utilize chemical substrate probes for analysis of the FUNCTIONAL P-450 isozyme composition and the accompanying capacity of fetal hepatic and extrahepatic tissues to catalyze regioselective metabolism of environmental toxins and prototype chemical carcinogens. Two types of probe, both of which exhibit restricted isozyme specificity, will be used in these studies; a) enantiomeric warfarin which produces a range of hydroxylated products from the parent molecule, and b) a series of phenoxazone ethers which are oxidized to a common metabolite. As test substrates, benzo(Alpha)pyrene (BP) and 2-acetylaminofluorene (AAF) will be employed. The proposal is based on the hypothesis that patterns of biotransformation of the two classes of chemical probes (warfarin and the phenoxazone ethers) will be highly predictive for the specific biotransformation of test substrates (BP and AAF). The hypothesis will be tested by 1) determining the goodness of fit for correlations of analyzed metabolic pathways under a variety of conditions and after perturbation by a series of regulatory agents, 2) making predictions based on the goodness of fit, and finally, 3) testing the predictability by analyzing tissues of unknown isozymic composition with the chemical probes and determining the degree to which these analyses predict BP and AAF metabolite profiles within the same tissues. The long-range goal of these investigations is to enable the ascertainment of P-450-dependent biotransforming and bioactivating capacities of fetal/embryonic tissues and others for which isolation and purification of the isozymic forms is impractical.