ToxSci Advance Access originally published online on September 4, 2008
Toxicological Sciences 2008 106(2):339-349; doi:10.1093/toxsci/kfn174
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Role of Nrf2 and Oxidative stress on Fenofibrate-Induced Hepatocarcinogenesis in Rats
,1,
* 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
Division of Pathology, National Institute of Health Sciences, 18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Department of 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
1 To whom correspondence should be addressed. Fax: +81-42-367-5771. E-mail: j_nisimr{at}cc.tuat.ac.jp.
Received July 1, 2008; accepted August 13, 2008
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Abstract |
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Regional specific relationships between oxidative stress and the development of glutathione S-transferase placental form (GST-P)–positive or GST-P–negative lesions in rats, induced by fenofibrate (FF), a peroxisome proliferator, were examined using a two-stage hepatocarcinogenesis model in F344 rats. Animals were initiated with a single ip injection of 200 mg/kg N-diethylnitrosamine (DEN) and from 2 weeks later were fed a diet containing 3000 or 0 ppm FF for 28 weeks. Animals were subjected to a two-third partial hepatectomy at week 3 and sacrificed at week 28. The development of hepatocellular proliferative lesions, which were mainly attributed to GST-P–negative lesions, was significantly increased in the FF-treated groups. Immunohistochemically, GST-P–positive lesions were devoid of intracytoplasmic nuclear factor-erythroid 2–related factor 2 (Nrf2) expression, whereas GST-P–negative lesions expressed higher levels of cytoplasmic Nrf2. On the other hand, nuclear accumulation of Nrf2 was observed in some cells of GST-P–positive lesions that were negative for Nrf2 in the cytoplasm and in GST-P–negative lesions of the DEN-FF group that were positive for Nrf2 in the cytoplasm. The mRNA expression levels of Gpx2 or Gsta2, Nrf2-inducible enzymes, were increased in GST-P–positive tumors or GST-P–positive lesions, respectively. These results suggest that the activation of Nrf2, due to nuclear translocation, occurs in the GST-P–positive lesions. In addition, the development of continuous oxidative stress was identified by mRNA expression analyses as well as by measurements of GST activity and 8-hydroxydeoxyguanosine. These results suggest that the relative inhibition of nuclear translocation of Nrf2 in GST-P–negative lesions aggravated the condition of oxidative stress in the liver of rats given FF, resulting in enhanced tumor promotion in FF-induced hepatocarcinogenesis.
Key Words: peroxisome proliferator; fenofibrate; rat; liver; hepatocarcinogenesis; GST-P; oxidative stress; laser microdissection; Nrf2.
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