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Xenobiotic Metabolism


In the present study, excreta were collected from mice receiving one of the three 14C-labeled compounds. Comparisons of elimination rates and routes and profiles of metabolites excreted in urine were performed between relevant treatment groups. Results indicated that metabolism of each of the three substrates was not appreciably altered between either transgenic line and the respective wildtype strain. Thus, the inherent ability of Tg.AC and p53+/- mice to metabolize xenobiotics does not appear to be a factor in data interpretation of toxicity studies using either of these transgenic mouse lines. Current work involves characterization of the xenobiotic-metabolizing capabilities of the Tg.AC and p53+/- mouse lines at the enzymatic protein level. Expression levels of several cytochrome p450 isozymes in the transgenic mouse lines are being compared with those of their respective wildtypes.

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Phenolphthalein (PT), used in over-the-counter laxatives, was recently identified in an NTP bioassay as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), may be a species responsible for at least part of the toxicity/carcinogenicity of PT. For example, formation of free radicals as a result of redox cycling of PT-CAT and the quinone present a potential carcinogenesis mechanism. PT-CAT is a substrate for catechol-O-methyltransferase (COMT), which inactivates reactive catechol metabolites of a number of molecules, including those of the hormone estradiol. In addition, PT-CAT is a potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s, which suggests that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis. To test this hypothesis, a study was performed to determine if PT increases the incidence of estrogen-induced kidney tumors in male hamsters. There was no increase in the number of macroscopic kidney nodules following 6 months of treatment with estradiol and PT. There was, however, a significant increase in the number of microscopic nodules in the estradiol plus high PT dose group indicating that PT-treatment may have an effect on hormonally-induced tumors.The use of transgenic animals, such as v-Ha-ras activated (Tg.AC) and p53+/- mice, offers promise for a rapid and sensitive assay for chemical carcinogenicity. The carcinogenic potential of many compounds is dependent on their metabolism to reactive intermediates; therefore it is critical that metabolism of xenobiotics be uncompromized by the altered genome in these model systems.
Recent work tests the generally held assumption that xenobiotic metabolism in the Tg.AC and p53+/- mouse is not inherently different from their respective wildtypes, the FVB/N and C57BL/6 mouse strains by comparing benzene, ethoxyquin, and methacrylonitrile metabolism. Together, use of these substrates offers the opportunity to examine arene oxide formation, aromatic ring opening, hydroxylation, epoxidation, O-deethylation, and a number of conjugation reactions.

Burka, Leo
DHHS/NIH - National Institute of Environmental Health Sciences
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