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

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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