THE MECHANISM OF STEATOSIS IN CHRONIC HEPATITIS : THE ROLE IN HEPATOCARCINOGENESIS.

丙型肝炎病毒感染后发生肝癌的机制尚不清楚。一种可能性是参与了氧化应激，氧化应激可以产生基因突变和严重的染色体变化，并有助于癌症的发展。我们最近发现，丙型肝炎病毒的核心蛋白在很长一段时间后，会在转基因小鼠中诱导肝细胞癌，并伴有明显的肝脏脂肪变性，但没有炎症反应，这表明丙型肝炎病毒直接参与了肝癌的发生。为了阐明肝细胞癌发生前的生化事件，我们在一个丙型肝炎病毒相关的小鼠模型中检测了氧化应激和氧化还原动态平衡的几个参数。对于3到12个月大的幼鼠，转基因和非转基因对照小鼠肝组织匀浆中磷脂酰胆碱和磷脂酰乙醇胺的过氧化氢水平没有显著差异。相比之下，在旧核GE…中，PCOOH水平增加了180%16个月以上的Ne转基因小鼠更多。同时，同一小鼠体内过氧化氢酶活性显著升高，总谷胱甘肽和还原型谷胱甘肽水平显著降低。化学发光法的直接原位测定显示，即使在年轻的转基因小鼠中，氢过氧化物的生成量也增加了170%，这表明在年轻的小鼠中，氢过氧化物量过多，但立即被激活的清除系统清除。电子显微镜下可见脂褐素颗粒，次级溶酶体携带多种细胞器，线粒体双膜结构破坏，PCR分析显示线粒体DNA缺失。有趣的是，酒精导致转基因小鼠PCOOH水平显著增加，提示酒精和丙型肝炎在肝癌发生中具有协同作用。因此，在没有炎症的情况下，丙型肝炎病毒核心蛋白改变了肝脏的氧化/抗氧化状态，从而可能有助于或至少部分促进丙型肝炎病毒感染的肝细胞癌的发展。较少

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 the core protein of HCV induces, after a long period, 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 prior to 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 aged 3 to 12 months, there was no significant difference in the levels of hydroperoxides of phosphatidylcholine (PCOOH) and phosphatidylethanolamine in liver tissue homogenates between transgenic and non-transgenic control mice. In contrast, PCOOH level was increased by 180% in old core ge … More ne transgenic mice aged over 16 months. Concurrently, there was a significant increase in the catalase activity, and 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 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 thereby may contribute to or facilitate, at least partly, the development of HCC in HCV infection. Less