Iron chelators and iron toxicity.
Iron chelation may offer new approaches to the treatment and prevention of alcoholic liver disease. With chronic excess, either iron or alcohol alone may individually injure the liver and other organs. In combination, each exaggerates the adverse effects of the other. In alcoholic liver disease, both iron and alcohol contribute to the production of hepatic fibrosis through their effects on damaged hepatocytes, hepatic macrophages, hepatic stellate cells, and the extracellular matrix. The pivotal role of iron in these processes suggests that chelating iron may offer a new approach to arresting or ameliorating liver injury. For the past four decades, deferoxamine B mesylate has been the only iron-chelating agent generally available for clinical use. Clinical experience with deferoxamine has demonstrated the safety and effectiveness of iron chelation for the prevention and treatment of iron overload. Determined efforts to develop alternative agents have at last resulted in the development of a variety of candidate iron chelators that are now in or near clinical trial, including (a) the hexadentate phenolic aminocarboxylate HBED [N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid], (b) the tridentate desferrithiocin derivative 4'-OH-dadmDFT [4'-hydroxy-(S)-desazadesmethyl-desferrithiocin; (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-thiazolecarboxylic acid], (c) the tridentate triazole ICL670A [CGP72 670A; 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid], and (d) the bidentate hydroxypyridin-4-one deferiprone [L1, CP20; 1,2-dimethyl-3-hydroxypyridin-4-one]. These agents may provide new pharmacological means of averting or ameliorating liver damage in alcoholic liver disease by binding, inactivating, and eliminating the reactive forms of iron that contribute to oxidative injury of cellular components, are involved in signal transduction, or both.
Brittenham
Gary M
GM
Departments of Pediatrics and Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. gmb31@columbia.edu
D000437:Alcoholism / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000627:therapeutic use; D019190:Iron Overload / Q000150:complications / Q000628:therapy; D008104:Liver Cirrhosis, Alcoholic / Q000209:etiology; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000517:prevention & control
D007502:Iron Chelating Agents; D007501:Iron