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

丙型肝炎病毒（HCV）感染致肝癌的机制尚不明确。一种可能是与氧化应激有关，氧化应激可以产生基因突变和总体染色体改变，从而促进癌症的发展。我们最近的研究表明，HCV的核心蛋白在经过很长一段时间后，诱导肝脂肪变性明显但无炎症的转基因小鼠的肝细胞癌（HCC），这表明HCV直接参与肝癌的发生。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月龄的幼鼠，转基因和非转基因小鼠肝组织匀浆中磷脂酰胆碱（PCOOH）和磷脂酰乙醇胺的氢过氧化物水平无显著差异。相比之下，PCOOH水平在16月龄以上的老年转基因小鼠中增加了180%。同时，在同一小鼠中，过氧化氢酶活性显著增加，总谷胱甘肽和还原性谷胱甘肽水平降低。通过化学发光直接原位测定发现，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量产生，但在年轻小鼠中被激活的清除系统立即清除。电镜显示脂褐质颗粒，携带各种细胞器的次级溶酶体和线粒体双膜结构的破坏，PCR分析显示线粒体DNA缺失。有趣的是，酒精引起转基因小鼠PCOOH水平显著升高，提示酒精和HCV在肝癌发生中有协同作用。因此，在没有炎症的情况下，HCV核心蛋白改变了肝脏的氧化/抗氧化状态，从而可能至少部分地促进或促进HCV感染中HCC的发展。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