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Comparison of the Levels of Enzymes Involved in Drug Metabolism between Transgenic or Gene-knockout and the Parental Mice
Noritaka Ariyoshi
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Susumu Imaoka
Laboratory of Chemical Biology, Osaka City University Medical School, Osaka 545-8585, Japan
Kazuo Nakayama
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Yoshiki Takahashi
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Ken-Ichi Fujita
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Yoshihiko Funae
Laboratory of Chemical Biology, Osaka City University Medical School, Osaka 545-8585, Japan
Tetsuya Kamataki
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan, kamataki{at}pharm.hokudai.ac.jp
Drug-metabolizing enzymes are involved in the metabolic activation or detoxification of carcinogens. To evaluate animals developed as models for alternative carcinogenicity testing, we investigated whether or not a gene manipulation including the transgene of ras and the knocking out of a tumor suppressor gene such as p53 orXPA could alter the expression of representative drug-metabolizing enzymes directly or indirectly. Expression of several isoforms of cytochrome P450 (CYP) in the liver of rasH2, p53 ( +/- ), Tg.AC, and XPA (-/-) mice with or without treatment of prototype inducer, phenobarbital or 3-methylcholanthrene, was analyzed by Western immunoblotting in comparison with their parental strains of mice. In addition, the activities of 3 major phase II enzymes, UDP-glucronosyltransferase, sulfotransferase, and glutathione S-transferase, were compared between the gene-manipulated and the corresponding parental strains of mice. Results demonstrate that XPA gene knockout appeared to increase constitutive expression of CYP2B and CYP3A isoforms. Overexpression of human c-Ha-ras gene or p53 gene knockout appeared to increase constitutive UGT activity toward 4-nitrophenol. The content or activities of almost all other enzymes examined in the present study do not appear to be affected by the gene manipulation.
Key Words: Alternative models • carcinogenicity testing • cytochrome P450 isoform • p53 ( +/- ) • phase II enzymes • rasH2 • Tg.AC • XPA (-/-).
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Toxicologic Pathology, Vol. 29, No. 1 suppl,
161-172 (2001)
DOI: 10.1080/019262301753178573
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