Alcohol, iron-associated oxidative stress, and cancer.
Oxidative stress is recognized to play an important role in the initiation and promotion events of carcinogenesis. Alcoholic liver disease is associated with significant oxidative stress as well as the hepatic accumulation of iron, a transition element also documented to initiate oxidative stress. The combined prooxidant potential of ethanol and iron is at least additive and possibly synergistic with respect to inducing hepatocellular oxidative stress and antioxidant depletion. One cellular consequence of sustained oxidative stress and redox imbalance resulting from the combined actions of alcohol and iron is lipid peroxidation, resulting in the production of aldehydic products such as 4-hydroxy-2-nonenal, which has been linked to site-specific mutations of the p53 gene. In addition, the accumulation of iron in hepatic macrophage isolated from laboratory animals chronically ingesting alcohol is associated with activation of nuclear factor-kappa B and production of tumor necrosis factor-alpha, providing a proinflammatory cellular environment also favorable for initiation and promotion of carcinogenesis. Consequently, there is persuasive evidence that the potential of ethanol and iron to induce oxidative stress may be an important pathogenic mechanism for the increased occurrence of hepatocellular carcinoma in individuals with hepatic iron overload who ingest alcohol.
Petersen
Dennis R
DR
Department of Pharmaceutical Sciences, Box C238, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA. dennis.petersen@uchsc.edu
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D000431:Ethanol / Q000009:adverse effects*; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000502:physiology / Q000633:toxicity; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D009369:Neoplasms / Q000139:chemically induced* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*
D002492:Central Nervous System Depressants; D000431:Ethanol; D007501:Iron