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Hepatocarcinogenic Susceptibility of Fenofibrate and Its Possible Mechanism of Carcinogenicity in a Two-Stage Hepatocarcinogenesis Model of rasH2 Mice

¹ Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
² Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu 501-1193, Japan
³ Department of Applied Biological Science, United Graduate School of Agricultural Sciences, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan

Correspondence: Address correspondence to: Masaomi Kawai, Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; e-mail:m_kawai{at}cc.tuat.ac.jp.

Fenofibrate (FF) has previously been shown to induce hepatocellular neoplasia in a conventional mouse bioassay (NDA 1993), but there has been no report to examine the carcinogenic susceptibility of rasH2 mice to this chemical. In the present study, male rasH2 mice were subjected to a two-thirds partial hepatectomy (PH), followed by an N-diethylnitrosamine (DEN) initiation twenty-four hours after PH, and given a diet containing 0, 1200, or 2400 ppm FF for seven weeks. The incidences of preneoplastic foci were significantly increased in mice from the FF-treated groups. Immunohistochemistry revealed that significant increases in proliferating cell nuclear antigen (PCNA)-positive cells and cytokeratin 8/18 positive foci were observed in FF-treated groups. In addition, the transgene and several downstream molecules such as c-myc, c-jun, activating transcription factor 3 (ATF3), and cyclin D1 were overexpressed in these groups. These results suggest that the hepatocarcinogenic activity of rasH2 mice to FF can be detected in this hepatocarcinogenesis model and that up-regulation of genes for the ras/MAPK pathway and cell cycle was probably involved in the hepatocarcinogenic mechanism of rasH2 mice.

Key Words: rasH2 mouse • fenofibrate • cytokeratin 8/18 • liver

Abbreviations: ATF3, activating transcription factor 3 • DEHP, diethyl hexylphalate • DEN, N-diethylnitrosamine • ENU, N-ethyl-N-nitrosourea • FDA, Food and Drug Administration • FF, fenofibrate • KO, knockout • MAPK, mitogen activated protein kinase • PBS, phosphate-buffered saline • PCNA, proliferating cell nuclear antigen • PH, partial hepatectomy • PPAR, peroxisome proliferator-activated receptor • real-time RT-PCR, quantitative real-time reverse transcription-polymerase chain reaction • TG, transgenic

This version was published on December 1, 2008

Toxicologic Pathology, Vol. 36, No. 7, 950-957 (2008)
DOI: 10.1177/0192623308327118


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