Iron-induced oxidative stress promotes hepatic injury in hereditary hemochromatosis, which can be influenced by genetic traits affecting antioxidant enzymes. We assessed the influence of Ala16Val-superoxide dismutase 2, Pro198Leu-glutathione peroxidase 1, and –463G/A-myeloperoxidase genotypes (high activity for the Ala, Pro, and G alleles, respectively) on the risks of cirrhosis and hepatocellular carcinoma (HCC) in patients homozygous for the C282Y-hemochromatosis (HFE) gene mutation. Both the 2G-myeloperoxidase genotype and carriage of one or two copies of the Ala-superoxide dismutase 2 allele were more frequent in patients with cirrhosis or HCC. Patients cumulating these two genetic traits had higher rates of cirrhosis and HCC than other patients. Antioxid. Redox Signal. 15, 31–38.
BagA, BagN. Target sequence polymorphism of human manganese superoxide dismutase gene and its association with cancer risk: a review. Cancer Epidemiol Biomarkers Prev, 17:3298–3305. 2008.
3.
BrownKE, BruntEM, HeineckeJW. Immunohistochemical detection of myeloperoxidase and its oxidation products in Kupffer cells of human liver. Am J Pathol, 159:2081–2088. 2001.
4.
DegoulF, SuttonA, MansouriA, CepanecC, DegottC, FromentyB, BeaugrandM, VallaD, PessayreD. Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease. Gastroenterology, 120:1468–1474. 2001.
5.
DeugnierY. Iron and liver cancer. Alcohol, 30:145–150. 2003.
6.
DeugnierY, TurlinB. Pathology of hepatic iron overload. World J Gastroenterol, 13:4755–4760. 2007.
7.
HuYJ, DiamondAM. Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res, 63:3347–3351. 2003.
8.
JouihanHA, CobinePA, CookseyRC, HoaglandEA, BoudinaS, AbelED, WingeDR, McClainDA. Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Mol Med, 14:98–108. 2008.
9.
JungeB, CarrionY, BoscoC, GalleanoM, PuntaruloS, TapiaG, VidelaLA. Effects of iron overload and lindane intoxication in relation to oxidative stress, Kupffer cell function, and liver injury in the rat. Toxicol Appl Pharmacol, 170:23–28. 2001.
10.
KlebanoffSJ. Myeloperoxidase: friend and foe. J Leukoc Biol, 77:598–625. 2005.
11.
LlovetJM, FusterJ, BruixJ. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl, 10:S115–S120. 2004.
12.
NahonP, CharnauxN, FriandV, Prost-SquarcioniC, ZiolM, LievreN, TrinchetJC, BeaugrandM, GattegnoL, PessayreD, SuttonA. The manganese superoxide dismutase Ala16Val dimorphism modulates iron accumulation in human hepatoma cells. Free Radic Biol Med, 45:1308–1317. 2008.
13.
NahonP, SuttonA, PessayreD, RufatP, DegoulF, Ganne-CarrieN, ZiolM, CharnauxN, N'KontchouG, TrinchetJC, GattegnoL, BeaugrandM. Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death. Clin Gastroenterol Hepatol, 3:292–298. 2005.
14.
NahonP, SuttonA, RufatP, ZiolM, AkoucheH, LaguillierC, CharnauxN, Ganne-CarrieN, Grando-LemaireV, N'KontchouG, TrinchetJC, GattegnoL, PessayreD, BeaugrandM. Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis. Hepatology, 50:1484–1493. 2009.
15.
OsterreicherCH, DatzC, StickelF, HellerbrandC, PenzM, HoferH, WrbaF, PennerE, SchuppanD, FerenciP. Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis. J Hepatol, 42:914–919. 2005.
16.
PakakasamaS, ChenTT, FrawleyW, MullerC, DouglassEC, TomlinsonGE. Myeloperoxidase promotor polymorphism and risk of hepatoblastoma. Int J Cancer, 106:205–207. 2003.
17.
PiedrafitaFJ, MolanderRB, VansantG, OrlovaEA, PfahlM, ReynoldsWF. An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem, 271:14412–14420. 1996.
18.
PietrangeloA. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med, 350:2383–2397. 2004.
ReynoldsWF, ChangE, DouerD, BallED, KandaV. An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood, 90:2730–2737. 1997.
22.
StewartSF, LeathartJB, ChenY, DalyAK, RollaR, VayD, MottaranE, VidaliM, AlbanoE, DayCP. Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or liver fibrosis. Hepatology, 36:1355–1360. 2002.
23.
StickelF, OsterreicherCH, DatzC, FerenciP, WolfelM, NorgauerW, KrausMR, WrbaF, HellerbrandC, SchuppanD. Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis. Arch Intern Med, 165:1835–1840. 2005.
24.
SuttonA, ImbertA, IgoudjilA, DescatoireV, CazanaveS, PessayreD, DegoulF. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenet Genomics, 15:311–319. 2005.
25.
SuttonA, KhouryH, Prip-BuusC, CepanecC, PessayreD, DegoulF. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics, 13:145–157. 2003.
26.
SuttonA, NahonP, PessayreD, RufatP, PoireA, ZiolM, VidaudD, BargetN, Ganne-CarrieN, CharnauxN, TrinchetJC, GattegnoL, BeaugrandM. Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis. Cancer Res, 66:2844–2852. 2006.
27.
WallaceDC. Mitochondrial diseases in man and mouse. Science, 283:1482–1488. 1999.
28.
WeitzmanSA, WeitbergAB, ClarkEP, StosselTP. Phagocytes as carcinogens: malignant transformation produced by human neutrophils. Science, 227:1231–1233. 1985.
29.
YamakuraF, KobayashiK, FurukawaS, SuzukiY. In vitro preparation of iron-substituted human manganese superoxide dismutase: possible toxic properties for mitochondria. Free Radic Biol Med, 43:423–430. 2007.
30.
YangM, CobinePA, MolikS, NaranuntaratA, LillR, WingeDR, CulottaVC. The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2. EMBO J, 25:1775–1783. 2006.
