Alcohol and Iron as Cofactors in Hepatocellular Carcinoma

Abstract

Oxidative stress is recognized as a central mechanism in the initiation and promotion stages of carcinogenesis. The combined pro-oxidant potential of ethanol and iron ranges from additive to synergistic with respect to initiating hepatocellular oxidative stress through antioxidant depletion. Disorders such as hemochromatosis and alcoholic liver disease are associated with significant oxidative stress and the hepatic accumulation of iron, both of which are predisposing factors for development of hepatocellular carcinoma (HCC). Sustained oxidative stress and redox imbalance associated with exposure to alcohol and iron results in DNA damage and the activation of cellular transcription factors which, in turn, initiate or contribute to neoplastic progression of the liver. Evidence is now emerging that activation of the transcription factor nuclear factor-κB in hepatic macrophage plays a significant role in initiation and propagation of early malignant clones that eventually lead to the development of HCC. Consequently, there is persuasive evidence that the potential of ethanol and iron to induce oxidative stress is an important pathomechanism underlying development of HCC. This review summarizes recently published studies, which describe the cellular events and mechanisms potentially involved in initiation and progression of HCC in individuals experiencing oxidative stress as a consequence of hepatic iron accumulation and chronic alcohol ingestion.