ToxSci Advance Access published online on January 29, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm011
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Effect of Fenofibrate on Oxidative DNA Damage and on Gene Expression Related to Cell Proliferation and Apoptosis in Rats
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* Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
Biochemistry and Biotechnology, United Graduate School of Agricultural Sciences, Tokyo, University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
Division of Pathology, National Institute of Health Sciences, 18-1 Kamiyoga, Setagaya-ku, 158-8501 Tokyo, Japan
¶ Corresponding author: Jihei Nishimura, Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan, Phone and Fax: +81-42-367-5771, E-mail address: j_nisimr{at}cc.tuat.ac.jp
Received October 11, 2006; accepted January 18, 2007
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Abstract |
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To investigate the relationship between fenofibrate (FF) and oxidative stress, enzymatic, histopathological, and molecular biological analyses were performed in the liver of male F344 rats fed 2 doses of FF (Experiment 1; 0 and 6,000 ppm) for 3 weeks and 3 doses (Experiment 2; 0, 3,000 and 6,000ppm) for 9 weeks. FF-treatment increased the activity of enzymes such as CAT, CPT, FAOS, and catalase in the liver. However, it decreased those of superoxide dismutase in the liver in both experiments. Increased 8-OHdG levels in liver DNA and lipofuscin accumulation were observed in the treated rats of Experiment 2. In vitro measurement of reactive oxygen species (ROS) in rat liver microsomes revealed a dose-dependent increase due to FF treatment. Microarray (only Experiment 1) or real time RT-PCR analyses revealed that the expression levels of metabolism and DNA repair-related genes such as Aco, Cyp4a1, catalase, Yc2, Gpx2, Apex1, Xrcc5, Mgmt, Mlh1, Gadd45a, and Nbn were increased in FF-treated rats. These results provide evidence of a direct or indirect relationship between oxidative stress and FF treatment. In addition, increases in the expression levels of cell cycle-related genes such as Chek1, Cdc25a, and Ccdn1; increases in the expression levels of cell proliferation-related genes such as Hdgfrp3 and Vegfb; and fluctuations in the expression levels of apoptosis-related genes such as Casp11 and Trp53inp1 were observed in these rats. This suggests that cell proliferation induction, apoptosis suppression, and DNA damage due to oxidative stresses are probably involved in the mechanism of hepatocarcinogenesis due to FF in rats.
Key Words: Peroxisome proliferators-activated receptor alpha agonist; Fenofibrate; Rat; Liver; Oxidative stress; DNA damage; Hepatocarcinogenesis; ROS.