Nishimura Jihei, Dewa Yasuaki, Okamura Toshiya, Jin Meilan, Saegusa Yukie, Kawai Masaomi, Umemura Takashi, Shibutani Makoto, Mitsumori Kunitoshi
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Toxicol Sci. 2008 Dec;106(2):339-49. doi: 10.1093/toxsci/kfn174. Epub 2008 Sep 4.
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.
利用F344大鼠的两阶段肝癌发生模型，研究了过氧化物酶体增殖剂非诺贝特（FF）诱导的大鼠氧化应激与谷胱甘肽S-转移酶胎盘型（GST-P）阳性或GST-P阴性病变发展之间的区域特异性关系。动物单次腹腔注射200mg/kg N-二乙基亚硝胺（DEN）启动实验，2周后开始喂食含3000或0ppm FF的饲料，持续28周。动物在第3周接受三分之二部分肝切除术，并在第28周处死。FF处理组中主要归因于GST-P阴性病变的肝细胞增殖性病变的发展显著增加。免疫组织化学分析显示，GST-P阳性病变缺乏细胞质内核因子红系2相关因子2（Nrf2）表达，而GST-P阴性病变表达较高水平的细胞质Nrf2。另一方面，在细胞质中Nrf2阴性的GST-P阳性病变的一些细胞以及细胞质中Nrf2阳性的DEN-FF组的GST-P阴性病变中观察到Nrf2的核积累。Nrf2诱导酶Gpx2或Gsta2的mRNA表达水平分别在GST-P阳性肿瘤或GST-P阳性病变中增加。这些结果表明，由于核转位，Nrf2在GST-P阳性病变中被激活。此外，通过mRNA表达分析以及GST活性和8-羟基脱氧鸟苷的测量确定了持续氧化应激的发展。这些结果表明，GST-P阴性病变中Nrf2核转位的相对抑制加重了给予FF的大鼠肝脏中的氧化应激状况，导致FF诱导的肝癌发生中肿瘤促进作用增强。
