Metabolism, distribution, and elimination are often critical elements in determining the toxic effects of chemicals. Extrapolation of results from animal studies to predict possible human health effects requires knowledge of metabolic pathways and of in vivo kinetic behavior. Investigation of mechanistic aspects of metabolic processes allows greater understanding of how metabolism of a xenobiotic might lead either to detoxification or to a reactive metabolite with greater toxicity. As more is learned about mechanisms of metabolism, more accurate predictions of possible metabolic pathways for new compounds should be possible. In the past year studies on 2,4-D, a widely used herbicide, showed striking differences in disposition and elimination, but not metabolism, between male and female rats. these studies suggest that female rats may be more susceptible to toxic effects of 2,4-D, however most studies on this peroxisome proliferator have been performed in males. The relevance of this observation to human health remains to be determined. Metabolism and distribution studies on nalidixic acid (NAL), an antibacterial agent, suggest the possibility that selective accumulation of a reactive species in the preputial glands of male rats accounts for the selective tumorigenicity of this chemical. A novel metabolite was identified as 6-hydroxyNAL glucuronide. NAL was shown to be a weak inducer of drug metabolizing enzymes following 1 week of exposure. As part of a study on isoprene, a rubber monomer, 2-methyl-2-hydroxy-3- butenoic acid was synthesized to confirm its identification as the major urinary metabolite. Reaction products between isoprene monoepoxide and N-acetylcysteine were prepared to determine if mercapturic acids were urinary metabolites. Overall it appears that the metabolite profile is considerably different from butadiene, the desmethyl analog and rodent carcinogen.
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