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

Noritaka Ariyoshi, S. Imaoka, K. Nakayama, Y. Takahashi, K. Fujita, Y. Funae, T. Kamataki

Research output: Contribution to journalArticle

9 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 numberSUPPL.
DOIs
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Gene Knockout Techniques
Metabolism
Knockout Mice
Genes
Enzymes
Pharmaceutical Preparations
Protein Isoforms
Sulfotransferases
Cytochrome P-450 CYP3A
Uridine Diphosphate
Methylcholanthrene
ras Genes
p53 Genes
Phenobarbital
Glutathione Transferase
Tumor Suppressor Genes
Transgenes
Carcinogens
Cytochrome P-450 Enzyme System
Western Blotting

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice. / Ariyoshi, Noritaka; Imaoka, S.; Nakayama, K.; Takahashi, Y.; Fujita, K.; Funae, Y.; Kamataki, T.

In: Toxicologic Pathology, Vol. 29, No. SUPPL., 2001, p. 161-172.

Research output: Contribution to journalArticle

Ariyoshi, Noritaka ; Imaoka, S. ; Nakayama, K. ; Takahashi, Y. ; Fujita, K. ; Funae, Y. ; Kamataki, T. / Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice. In: Toxicologic Pathology. 2001 ; Vol. 29, No. SUPPL. pp. 161-172.
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