Hepatitis Induces Oxidative Dna Damage Of Importance For Hepatocarcinogenesis

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The necroinflammatory reaction seen in livers with viral hepatitis is the result of a host immune response to viral antigens.14 Recruited leukocytes and macrophages release reactive oxygen species in areas of infection, which create necrosis of target hepatocytes. The enhanced oxidative stress overwhelms antioxidant defense mechanisms and leads to damage of crucial macromolecules, including DNA. 8-oxo-2'-deoxyguanosine (8-oxo-dG) is continuously produced in liver tissue but in the case of a normal liver, is quickly removed by DNA repair enzymes. However, in chronic hepatitis, oxidative stress is enhanced and cell proliferation increased, which enables DNA replication to occur before the repair of genetic lesions is complete, resulting in mutations. This concept has been tested in the hepatitis B-virus (HBV) transgenic mouse animal model. These mice overexpress the HBV large envelope protein, leading to necrosis, inflammation, and subsequent development of HCC.12 A significant accumulation of 8-oxo-dG was found in areas with pronounced inflammation and liver cell proliferation, and the levels of 8-oxo-dG correlated to the extent of the liver disease.8

Thus, experimental data strongly indicate that increased oxidative stress is an important pathogenic mechanism in hepatitis-induced liver damage, and these results are supported by clinical data on humans with hepatitis B and C. In these patients, plasma levels of vitamin E were decreased as compared with that of healthy controls, indicating depletion of antioxidants secondary to the hepatitis infection.21,23 Likewise, in an assay using the plasma ratio of oxidized and reduced ubiquinone as a marker of oxidative stress,20 patients with hepatitis were found to have a significantly increased ratio as compared with healthy controls.22 In a prospective randomized double-blind crossover study, patients with chronic hepatitis C refractory to alpha-interferon therapy were treated with high doses of vitamin E, which significantly reduced the serum activities of aminotransferases, indicating a reduction of the liver damage.50 These findings indicate that enhanced free radical production may be of importance in the pathogenesis of virus-associated liver cancer development.

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