Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice

Noritaka Ariyoshi, Susumu Imaoka, Kazuo Nakayama, Yoshiki Takahashi, Ken Ichi Fujita, Yoshihiko Funae, Tetsuya Kamataki

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)

Abstract

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 or XPA 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.

Original languageEnglish
Pages (from-to)161-172
Number of pages12
JournalToxicologic Pathology
Volume29
Issue number1
Publication statusPublished - 2001
Externally publishedYes

Keywords

  • Alternative models
  • Carcinogenicity testing
  • Cytochrome P450 isoform
  • Phase II enzymes
  • Tg.AC
  • XPA (-/-)
  • p53 ( /-)
  • rasH2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Toxicology
  • Cell Biology

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