Iron-induced oxidant stress in alcoholic liver fibrogenesis
Introduction
Iron is a vital micronutrient, but its chemistry greatly limits its utilization and also sets the basis for its toxicity. The capacity of readily exchanging electrons in aerobic conditions makes iron essential for fundamental cell functions, such as DNA synthesis, transport of oxygen and electrons, and cell respiration. On the other hand, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. In fact, a number of disease states, due to both a primary defect of iron metabolism (e.g., hemochromatosis) and acquired causes (e.g., iron-loading anemias, alcoholic and viral liver disease) (Fig. 1), are pathogenically linked to excess iron. In many of these conditions, iron-removal therapy is an effective lifesaving strategy. Untreated iron overload disease leads to organ fibrosis and cancer. It is now clear that iron toxicity, when acting on its own or in concert with other hepatotoxins (e.g., alcohol), is mediated by oxidative stress–driven damage and fibrogenesis (Pietrangelo, 1996).
Section snippets
Iron, reactive oxygen species, and oxidative stress
In every cell, during its normal life in aerobic conditions, a small amount of the consumed oxygen is reduced in a specific way, yielding highly reactive chemical entities, collectively called reactive oxygen species. Reactive oxygen species include a variety of molecular species, such as hydrogen peroxide (H2O2), singlet molecular oxygen (1O2), hydroxyl (OH−), superoxide (O2−), alkoxyl (RO−), peroxyl (ROO−), and nitric oxide (NO−) radicals, highly heterogeneous in terms of reactivity against
Iron, alcohol, and hepatic fibrogenesis
Hepatic fibrosis is a dynamic process, from chronic liver damage to cirrhosis. It is characterized by excessive accumulation of extracellular matrix components in the liver caused by both markedly increased production (fibrogenesis) and unbalanced degradation (fibrolysis) (Friedman, 1993). Acute insults to liver cells, regardless of their intrinsic nature, will disrupt the equilibrium between extracellular matrix and hepatocytes, causing release of bioactive molecules from extracellular matrix,
Acknowledgements
This work was supported by grants from the European Community and Ministero dell'Università della Ricerca Scientifica e Tecnologica, MURST.
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