This Article Free Full Text (Free PDF) Free References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Ariyoshi, N. Articles by Kamataki, T. Search for Related Content PubMed PubMed Citation Articles by Ariyoshi, N. Articles by Kamataki, T. Social Bookmarking                         What's this?

Comparison of the Levels of Enzymes Involved in Drug Metabolism between Transgenic or Gene-knockout and the Parental Mice

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 (-/-).

Toxicologic Pathology, Vol. 29, No. 1 suppl, 161-172 (2001)
DOI: 10.1080/019262301753178573


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				R. Elsby, N. R. Kitteringham, C. E. Goldring, C. A. Lovatt, M. Chamberlain, C. J. Henderson, C. R. Wolf, and B. K. Park Increased Constitutive c-Jun N-terminal Kinase Signaling in Mice Lacking Glutathione S-Transferase Pi J. Biol. Chem., June 13, 2003; 278(25): 22243 - 22249. [Abstract] [Full Text] [PDF]