Development in Patients with Alcohol-Induced Cirrhosis Hepatic Iron Accumulation and Hepatocellular Carcinoma Genetic Polymorphisms in Antioxidant Enzymes Modulate

Manganese superoxide dismutase (MnSOD) converts the superoxide anion into H2O2, which, unless it is detoxified by glutathione peroxidase 1 (GPx1), can increase hepatic iron and can react with iron to form genotoxic compounds. We investigated the role of Ala/Val-MnSOD and Pro/Leu-GPx1 polymorphisms on hepatic iron accumulation and hepatocellular carcinoma development in patients with alcoholic cirrhosis. Genotypes were determined in 162 alcoholic patients with cirrhosis but without hepatocellular carcinoma initially, who were prospectively followed up for hepatocellular carcinoma development. We found that patients with two Val-MnSOD alleles (slow H2O2 production) and two Pro-GPx1 alleles (presumably quick H2O2 detoxification) had a lower risk of hepatocellular carcinoma development than other patients (C trend test, P = 0.001; log-rank, P = 0.0009). Indeed, hepatocellular carcinoma percentage was 0% in subjects with this ‘‘2Val-MnSOD/2Pro-GPx1’’ genotype versus 16%, 27%, and 32% in ‘‘2Val-MnSOD/1or2Leu-GPx1,’’ ‘‘1or2AlaMnSOD/2Pro-GPx1,’’ and ‘‘1or2Ala-MnSOD/1or2Leu-GPx1’’ patients, respectively. The percentage of patients with stainable hepatic iron increased progressively with these genotypic associations: 22%, 28%, 50%, and 53%, respectively (C trend test, P = 0.005). Stainable iron was a risk factor for hepatocellular carcinoma (log-rank, P = 0.0002; relative risk, 3.40). In conclusion, polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in French alcoholic patients with cirrhosis. (Cancer Res 2006; 66(5): 2844-52)