title: Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Moriya
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Santa
authors.forename: Y
authors.initials: Y
authors.lastname: Shintani
authors.forename: H
authors.initials: H
authors.lastname: Fujie
authors.forename: H
authors.initials: H
authors.lastname: Miyoshi
authors.forename: T
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: T
authors.initials: T
authors.lastname: Miyazawa
authors.forename: K
authors.initials: K
authors.lastname: Ishibashi
authors.forename: T
authors.initials: T
authors.lastname: Horie
authors.forename: K
authors.initials: K
authors.lastname: Imai
authors.forename: T
authors.initials: T
authors.lastname: Todoroki
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000378:metabolism* / Q000821:virology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000821:virology; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014758:Viral Core Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione