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Carcinogenesis |
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 [K. M., Y. S., H. F., H. M., T. Ts., S. K., K. K.]; Biodynamic Chemistry Laboratory, Tohoku University Graduate School of Life Science and Agriculture, Sendai 980-8575 [K. N., T. M.]; Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033 [T. S., K. Im.]; Daiichi Pharmaceuticals, Tokyo 134-0081 [K. Is.]; Department of Pharmacology, University of Chiba, Chiba 260-8670 [T. H.]; and Department of Laboratory Medicine, Keio University School of Medicine, Tokyo 160-8582 [T. To.], Japan
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.
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