Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis.
Manganese superoxide dismutase (MnSOD) converts the superoxide anion into H(2)O(2), 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 H(2)O(2) production) and two Pro-GPx1 alleles (presumably quick H(2)O(2) detoxification) had a lower risk of hepatocellular carcinoma development than other patients (chi(2) 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," "1or2Ala-MnSOD/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 (chi(2) 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.
Sutton
Angela
A
UPRES 3410, UFR Santé, Médecine et Biologie Humaine, Université Paris XIII, Bobigny, France. angela.sutton@jvr.ap-hop-paris.fr
Nahon
Pierre
P
Pessayre
Dominique
D
Rufat
Pierre
P
Poiré
Aurélie
A
Ziol
Marianne
M
Vidaud
Dominique
D
Barget
Nathalie
N
Ganne-Carrié
Nathalie
N
Charnaux
Nathalie
N
Trinchet
Jean-Claude
JC
Gattegno
Liliane
L
Beaugrand
Michel
M
D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D007501:Iron; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human