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Hepatic drug metabolizing enzymes induced by clofibrate in rasH2 mice

N Katsutani1, T Sekido, T Aoki

  • 1Department of Developmental Safety Assessment Research, Eisai Company, Gifu, Japan. n-katsutani@hhc.eisai.co.jp

Toxicology Letters
|May 18, 2000
PubMed

Insights

Gene integration in rasH2 mice did not alter hepatic drug metabolizing enzyme activities or responses to clofibrate treatment. The study evaluated changes in cytochrome P450 and peroxisome proliferation markers.

Area of Science:

  • Pharmacology
  • Toxicology
  • Genetics

Background:

  • Transgenic mice (rasH2) carrying the human c-Ha-ras gene are used to study carcinogenicity.
  • Hepatic drug metabolizing enzymes play a crucial role in xenobiotic metabolism and detoxification.
  • Understanding the impact of gene integration on these enzymes is vital for interpreting toxicity studies.

Purpose of the Study:

  • To investigate the effect of clofibrate, a peroxisome proliferator, on hepatic drug metabolizing enzyme activities in rasH2 mice.
  • To evaluate whether the integration of the human c-Ha-ras gene influences these enzyme activities and the response to clofibrate.

Main Methods:

  • Male and female rasH2 (Tg) and non-transgenic (non-Tg) littermates were treated with clofibrate (500 mg/kg) or vehicle for 12 days.
  • Liver homogenates and microsomes were analyzed for cytochrome P450 (CYP) and cytochrome b5 content and activities.
  • Enzyme activities related to peroxisome proliferation, such as catalase and carnitine palmitoyl transferase, were determined.

Main Results:

  • Clofibrate treatment significantly increased relative liver weights, CYP4A content, and the activities of catalase and carnitine palmitoyl transferase in both Tg and non-Tg mice.
  • These increases were comparable between the transgenic and non-transgenic groups.
  • No significant differences in CYP and cytochrome b5 content and activities were observed between Tg and non-Tg mice, both in vehicle-treated and clofibrate-treated groups.

Conclusions:

  • Gene integration of human c-Ha-ras in rasH2 mice does not alter basal hepatic drug metabolizing enzyme activities.
  • The response of hepatic drug metabolizing enzymes and peroxisome proliferation markers to clofibrate is not affected by the presence of the integrated human c-Ha-ras gene.
  • These findings suggest that rasH2 mice are a suitable model for evaluating the effects of xenobiotics without confounding effects from the transgene on drug metabolism.

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