Journal Article

Role of Nrf2 and Oxidative stress on Fenofibrate-Induced Hepatocarcinogenesis in Rats

Jihei Nishimura, Yasuaki Dewa, Toshiya Okamura, Meilan Jin, Yukie Saegusa, Masaomi Kawai, Takashi Umemura, Makoto Shibutani and Kunitoshi Mitsumori

in Toxicological Sciences

Volume 106, issue 2, pages 339-349
Published in print December 2008 | ISSN: 1096-6080
Published online September 2008 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfn174
Role of Nrf2 and Oxidative stress on Fenofibrate-Induced Hepatocarcinogenesis in Rats

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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.

Keywords: peroxisome proliferator; fenofibrate; rat; liver; hepatocarcinogenesis; GST-P; oxidative stress; laser microdissection; Nrf2

Journal Article.  6663 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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