National Toxicology Program

National Toxicology Program

Comparative Xenobiotic Metabolism Between Tg.AC and p53 Deficient Mice and their Respective Wild Types

J M Sanders, L T Burka, J E Fossett, and H B Matthews.

NIEHS, Research Triangle Park, NC.

The use of transgenic animals, such as Ha-ras activated (Tg.AC) and p53-deficient mice, offers great promise as a model for a more rapid and possibly more sensitive method for assessing chemical carcinogenicity. Since metabolism through reactive intermediates is a critical factor in the carcinogenic potential of many compounds, it is of interest to compare xenobiotic metabolism between transgenic animals and their corresponding wild types. Consequently, the present work has examined the comparative metabolism of three xenobiotics through a series of metabolic pathways by Tg.AC and p53-deficient mice and their respective parent strains, FVB and C57BL/6. The metabolism of each of the three substrates, benzene, ethoxyquin, and methacrylonitrile has been well characterized. 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. Most of the metabolites formed from these chemicals are excreted in urine. In the present study, excreta was collected for up to 72 hr from mice receiving single oral doses of 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 altered between Tg.AC and p53-deficient mice and their respective parent strains, FVB and C57BL/6 mice.

The Toxicologist Vol. 42 abstract # 1636, 1998

NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.