Comparative xenobiotic metabolism between Tg.AC and p53+/- genetically altered mice and their respective wild types

The use of transgenic animals, such as v-Ha-ras activated (Tg.AC) and p53+/ - mice, offers great promise for a rapid and more sensitive assay for chemi cal carcinogenicity. Some carcinogens are metabolically activated; therefor e, it is critical that the altered genome of either of these model systems does not compromise their capability and capacity for metabolism of xenobio tics. The present work tests the generally held assumption that xenobiotic metabolism in the Tg.AC and p53+/- mouse is not inherently different from t hat of the respective wild type, the FVB/N and C57BL/6 mouse, by comparing each genotype's ability to metabolize benzene, ethoxyquin, or methacrylonit rile. Use of these representative substrates offers the opportunity to exam ine arene oxide formation, aromatic ring opening, hydroxylation, epoxidatio n. O-deethylation, and a number of conjugation reactions. Mice were treated by gavage with C-14-labeled parent compound. excreta were collected, and e limination routes and rates, as well as C-14-derived metabolite profiles in urine, were compared between relevant treatment groups. Results of this st udy indicated that metabolism of the 3 parent compounds was not appreciably altered between either FVB/N and Tg.AC mise or C57BL/6 and p53+/-mice. Fur ther, expression of CYP1A2, CYP2E1, CYP3A, and GST-alpha in liver of naive genetically altered mice was similar to that of corresponding wild-type mic e. Thus, these results suggest that the inherent ability of Tg.AC and p53+/ - mice to metabolize xenobiotics is not compromised by their altered genome s and would not be a factor in data interpretation of toxicity studies usin g either transgenic mouse line.