Iron Overload Depletes Hepatic Antioxidants

Iron has been used as a model substance in the studies of oxidative liver damage, since iron is known to increase the production of free radicals and enhance oxidative stress.24,25 In humans, the most common diseases with iron overload are genetic hemochromatosis and transfusional iron overload. Genetic hemochromatosis is an inherited disorder of iron metabolism in which excess iron is absorbed via the gut and deposited in parenchymal organs, predominantly the liver.26,27 With time, deposition of intracellular iron in hepatocytes results in lipid peroxidation of cellular membranes, impairment of mitochondrial functions, leakage of lysosomal enzymes, and finally iron-induced necrosis (called sideronecrosis).26 Once sideronecrosis has occurred, Kupffer cells and lipocytes will become activated and collagen synthesis increased,28 eventually leading to fibrosis, cirrhosis, and an increased risk for the development of hepatocellular carcinoma.29-31

Feeding rats with dietary carbonyl iron will mimic the iron-loading pattern of the human disease, and is used as an animal model of precirrhotic hemochromatosis.32-34 In this model, iron was shown to enhance lipid peroxidation (determined as thiobarbituric acid reactive products)35,36 and deplete the hepatic contents of a-tocopherol,35 reduced ubiquinone-937 38 and ubiquinone-10.39 In another animal model using the ferrocene iron-loaded rat, breath ethane exhalation, as a marker of lipid peroxidation, was increased and dependent on the extent of iron overload.40 Plasma as well as hepatic a-tocopherol decreased with progressive iron loading and a significant depletion in hepatic ubiquinol-9 and -10 was noted.40

However, in spite of increased oxygen free radical production in iron-loaded livers, neither cirrhosis32,33 nor hepatocellular carcinoma34 have been encountered in animal models of dietary iron overload. In this respect, dietary iron overload may differ from parenterally administered iron dextran, the latter of which was found to act as a promoter in hepatocarcinogenesis in conjunction with diethylnitrosamine (DEN).41

In genetic hemochromatosis, the increased cancer risk does not persist if excess iron is removed before the development of cirrhosis,31 indicating that the cirrhosis may be a greater risk factor for developing hepatocellular carcinoma (HCC) than the iron overload per se. However, additional clinical data suggest that iron-induced oxidative stress may play a role in hepatocarcinogenesis apart from being an inducer of cirrhosis. In one study, livers with and without HCC were compared regarding their iron contents.19 Livers with HCC had increased iron deposits in the tissue surrounding the tumor, as compared with normal or cirrhotic livers without HCC, or livers with metastatic tumors, suggesting that long-term iron-induced oxidative stress may increase the risk for malignant transformation.

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