8-hydroxyguanosine and Liver-Cirrhosis

Cell culture studies and animal models point to an important role of oxidative/nitrosative stress in the pathogenesis of cerebral ammonia toxicity. However, it is unknown whether oxidative/nitrosative stress in the brain is also characteristic of hepatic encephalopathy (HE) in humans. We therefore analyzed post mortem cortical brain tissue samples from patients with cirrhosis dying with or without HE in comparison with brains from patients without liver disease. Significantly elevated levels of protein tyrosine-nitrated proteins, heat shock protein-27, and 8-hydroxyguanosine as a marker for RNA oxidation were found in the cerebral cortex of HE patients, but not of patients with cirrhosis but without HE. Glutamine synthetase (GS) activity was significantly decreased, whereas GS protein expression was not significantly affected. Protein expression of the glutamate/aspartate cotransporter was up-regulated in HE, whereas protein expression of neuronal and inducible nitric oxide synthases, manganese-dependent and copper/zinc-dependent superoxide dismutase, and glial glutamate transporter-1 were not significantly increased.. These data indicate that HE in patients with cirrhosis is associated with oxidative/nitrosative stress, protein tyrosine nitration, and RNA oxidation, suggesting a role of oxidative stress in the pathogenesis of HE in patients with cirrhosis.

Topics: Adult; Aged; Amino Acid Transport System X-AG; Biomarkers; Cerebral Cortex; Excitatory Amino Acid Transporter 2; Female; Glutamate-Ammonia Ligase; Guanosine; Hepatic Encephalopathy; HSP27 Heat-Shock Proteins; Humans; Liver Cirrhosis; Male; Middle Aged; Nitrates; Oxidative Stress; RNA; Tyrosine

8-Hydroxydeoxyguanosine (oh8dG) is a promutagenic DNA lesion produced by oxygen radicals. We examined alterations in the oh8dG level in human livers which have chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The oh8dG content in livers with chronic hepatitis was significantly higher than the oh8dG content in normal livers (P < 0.05). There was also a significant correlation between the oh8dG content in noncancerous liver tissues with individual serum alanine aminotransferase concentration (r = 0.515; P < 0.001). Thus, chronic inflammation in the liver produces oxidative DNA damage, which may increase the risk for genomic alterations causing hepatocarcinogenesis.

Topics: Alanine Transaminase; Carcinoma, Hepatocellular; Chronic Disease; DNA; DNA Damage; Evaluation Studies as Topic; Guanosine; Hepatitis; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Oxidation-Reduction; Reactive Oxygen Species; Risk Factors