Effects of Clofibrate in the CB6F1-TgHras2 Mice

• Published in: Journal of Toxicologic Pathology Vol. 15; no. 2; p. 111
• Main Authors: Aoki, Toyohiko, Imai, Toshio, Ando, Tomomi, Dodo, Tetsushi, Kerns, William D., Motooka, Satoru, Tsukidate, Kazuo
• Format: Journal Article
• Language: English; Japanese
• Published: Tokyo JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY 2002; The Japanese Society of Toxicologic Pathology; Japan Science and Technology Agency
• Subjects: c-Ha-ras; clofibrate; hepatocellular adenoma; peroxisome proliferator; rasH2 mouse
• ISSN: 0914-9198; 1881-915X; 1347-7404
• DOI: 10.1293/tox.15.111

The tumorigenic potential of clofibrate, a peroxisome proliferator, was evaluated in a 26-week bioassay using CB6F1-TgHras2 (rasH2) mice carrying a human prototype c-Ha-ras gene. Clofibrate was administered to rasH2 mice orally by gavage at doses of 0 (vehicle control), 125, 250 or 500 mg/kg/day for 26 weeks. Single i.p. injection of 75 mg/kg methyl nitrosourea (MNU) was given to additional rasH2 group as positive control. CB6F1 non-Tg-rasH2 (non-Tg) mice were given either vehicle or 500 mg/kg of clofibrate. In rasH2 mice receiving clofibrate, hepatocellular adenoma was observed in males; 0 (1/15), 125 (0/15), 250 (3/15), and 500 mg/kg (3/15), but not in females. Although the trend test was positive (p<0.01), there was no dose-response and no statistical significance for hepatocellular adenoma. There was no hepatocellular adenoma in non-Tg mice. Increased incidence of neoplastic lesions, e.g. thymic lymphomas, forestomach/skin tumors were found in MNU treated mice as expected. In conclusion, the tumorigenic potential of clofibrate was equivocal in this model, as there was a weak response in the male 250 and 500 mg/kg dose groups but no dose-response. These results indicated further validation of this model as an alternative to the 2-year rodent carcinogenicity bioassay for human carcinogenic safety assessment will be needed.