Understanding how a xenobiotic is metabolized, distributed, and eliminated is often critical to an appreciation of the toxic effect(s) of the compound. Further, extrapolation of results from animal testing to possible human health effects requires knowledge of metabolic pathways. The fidelity of the extrapolation is enhanced if the fate of a xenobiotic is known for both (all) species used in the extrapolation. Investigation of the 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 the possible metabolic pathways for new compounds should be possible. This group carried out studies on 1.2.3.-trichloropropane (TCP), saligenin cyclic o-tolyl phosphate (SCOTP), cyclohexanone oxime (CHOX) and furan in the past year. As part of our continuing study on the metabolism of TCP, an industrial solvent, we have identified 2-(S-gluthathionyl) malonic acid as a biliary metabolite. This metabolite could arise by a series of oxidations and episulfonium ion intermediates and points out the potential reactivity of this compound. The male reproductive toxicity of tri o- cresyl phosphate may be attributed to the metabolic formation of SCOTP. In a recently completed study to determine the in vivo half-life of this reactive compound, the blood half-life of SCOTP was found to be long enough to be formed in the liver and transported to the testes--the target tissue. CHOX was readily absorbed, distributed and eliminated after a single oral dose of 1, 10 or 30 mg/kg. The majority of the radioactivity was eliminated in 24 hr. Pharmacokinetic studies have shown that CHOX has a biological half life of less than 1 hr. Only 4-5% of a dermally administered dose was absorbed. Oral administration of furan decreased hepatic P-450 content and the activity of P-450-dependent enzymes. Metabolism dependent covalent binding of furan to microsomal protein indicates that P-450 IIE1 preferentially catalyzes the metabolic activation of furan.
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