Hepatocarcinogenic susceptibility of fenofibrate and its possible mechanism of carcinogenicity in a two-stage hepatocarcinogenesis model of rasH2 mice.
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.
Kawai
Masaomi
M
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan. m_kawai@cc.tuat.ac.jp
Jin
Meilan
M
Nishimura
Jihei
J
Dewa
Yasuaki
Y
Saegusa
Yukie
Y
Matsumoto
Sayaka
S
Taniai
Eriko
E
Shibutani
Makoto
M
Mitsumori
Kunitoshi
K
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods*; D004052:Diethylnitrosamine / Q000008:administration & dosage; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000008:administration & dosage / Q000633:toxicity*; D006498:Hepatectomy; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011519:Proto-Oncogenes; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric
D053538:Keratin-18; D053533:Keratin-8; D018809:Proliferating Cell Nuclear Antigen; D004052:Diethylnitrosamine; D020928:Mitogen-Activated Protein Kinases; D011345:Fenofibrate