ToxSci Advance Access published online on September 4, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn174
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Role of Nrf2 and oxidative stress on fenofibrate-induced hepatocarcinogenesis 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
Division of Pathology, National Institute of Health Sciences, 18-1 Kamiyoga, Setagaya-ku, 158-8501 Tokyo, 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
¶ 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 July 1, 2008; revision received August 12, 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 intraperitoneal injection of 200 mg/kg diethylnitrosamine and from 2 weeks later were fed a diet containing 3,000 or 0 ppm FF for 28 weeks. Animals were subjected to a two-thirds 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 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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