Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis

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 alteratio ns and contribute to cancer development, We recently showed that after a lo ng period, the core protein of HCV induces hepatocellular carcinoma (HCC) i n transgenic mice with marked hepatic steatosis but without inflammation, i ndicating 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 HC V-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, th ere was a significant increase in the catalase activity, and there were dec reases in the levels of total and reduced glutathione in the same mice. A d irect in situ determination by chemiluminescence revealed an increase in hy droperoxide products by 170% even in young transgenic mice, suggesting that hydroperoxides were overproduced but immediately removed by an activated s cavenger system in young mice. Electron microscopy revealed lipofuscin gran ules, secondary lysosomes carrying various cytoplasmic organelles, and disr uption of the double membrane structure of mitochondria, and PCR analysis d isclosed a deletion in mitochondrial DNA, Interestingly, alcohol caused a m arked 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 inflamm ation and may thereby contribute to or facilitate, at least in part, the de velopment of HCC in HCV infection.