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.