Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis.
Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis.
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发表时间：
2001-06
期刊：
影响因子：
11.2
通讯作者：
K. Moriya;K. Nakagawa;T. Santa;Y. Shintani;H. Fujie;H. Miyoshi;T. Tsutsumi;T. Miyazawa;K. Ishibashi;T. Horie;Kazuhiro Imai;T. Todoroki;S. Kimura;K. Koike
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作者：
K. Moriya;K. Nakagawa;T. Santa;Y. Shintani;H. Fujie;H. Miyoshi;T. Tsutsumi;T. Miyazawa;K. Ishibashi;T. Horie;Kazuhiro Imai;T. Todoroki;S. Kimura;K. Koike
丙型肝炎病毒（HCV）感染引起肝癌的机制尚不清楚。一种可能性是氧化应激的参与，它可以产生基因突变以及染色体的总体改变，并有助于癌症的发展。我们最近发现，经过很长一段时间，HCV的核心蛋白诱导肝细胞癌（HCC）的转基因小鼠具有显着的肝脂肪变性，但没有炎症，表明直接参与HCV在肝癌的发生。为了阐明HCC发生前的生化事件，我们在HCV相关HCC小鼠模型中检测了氧化应激和氧化还原稳态的几个参数。对于3-12月龄的幼龄小鼠，转基因和非转基因对照小鼠肝组织匀浆中磷脂酰胆碱（PCOH）和磷脂酰乙醇胺的过氧化氢水平无显著差异。相比之下，在> 16个月大的老年核心基因转基因小鼠中，PCOH水平增加了180%。同时，有一个显着的过氧化氢酶的活性增加，并在同一小鼠的总谷胱甘肽和还原型谷胱甘肽的水平下降。通过化学发光直接原位测定显示，即使在年轻的转基因小鼠中，氢过氧化物产物也增加了170%，这表明氢过氧化物过度产生，但在年轻小鼠中被激活的清除剂系统立即清除。电子显微镜显示脂褐质颗粒，次级溶酶体携带各种细胞质细胞器，线粒体的双膜结构的破坏，和PCR分析揭示了线粒体DNA的缺失。有趣的是，酒精导致转基因小鼠的PCOOH水平显着增加，这表明酒精和HCV在肝癌发生中存在协同作用。因此，HCV核心蛋白在没有炎症的情况下改变肝脏中的氧化剂/抗氧化剂状态，从而可能至少部分地促成或促进HCV感染中HCC的发展。
The mechanism of hepatocarcinogenesis in hepatitis C virus (HCV) infection is still undefined. One possibility is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations and contribute to cancer development. We recently showed that after a long period, the core protein of HCV induces hepatocellular carcinoma (HCC) in transgenic mice with marked hepatic steatosis but without inflammation, indicating a direct involvement of HCV in hepatocarcinogenesis. To elucidate the biochemical events before the development of HCC, we examined several parameters of oxidative stress and redox homeostasis in a mouse model of HCV-associated HCC. For young mice ages 3-12 months, there was no significant difference in the levels of hydroperoxides of phosphatidylcholine (PCOOH) and phosphatidylethanolamine in liver tissue homogenates between transgenic and nontransgenic control mice. In contrast, the PCOOH level was increased by 180% in old core gene transgenic mice > 16 months old. Concurrently, there was a significant increase in the catalase activity, and there were decreases in the levels of total and reduced glutathione in the same mice. A direct in situ determination by chemiluminescence revealed an increase in hydroperoxide products by 170% even in young transgenic mice, suggesting that hydroperoxides were overproduced but immediately removed by an activated scavenger system in young mice. Electron microscopy revealed lipofuscin granules, secondary lysosomes carrying various cytoplasmic organelles, and disruption of the double membrane structure of mitochondria, and PCR analysis disclosed a deletion in mitochondrial DNA. Interestingly, alcohol caused a marked increase in the PCOOH level in transgenic mice, suggesting synergism between alcohol and HCV in hepatocarcinogenesis. The HCV core protein thus alters the oxidant/antioxidant state in the liver in the absence of inflammation and may thereby contribute to or facilitate, at least in part, the development of HCC in HCV infection.