HEPATOTOXICITY INDUCED BY IRON OVERLOAD AND ALCOHOL - STUDIES ON THE ROLE OF CHELATABLE IRON, CYTOCHROME-P450 2E1 AND LIPID-PEROXIDATION

Background/Aims: Clinical experience and studies with experimental ani mal models indicate a synergistic hepatotoxic effect of dietary iron o verload and chronic alcohol ingestion. In order to elucidate the mecha nism underlying this synergism, we examined the hepatic levels of etha nol-inducible cytochrome P450 2E1, glutathione and malondialdehyde, an d the effect of iron chelation with desferrioxamine, in livers from ra ts treated with iron and/or ethanol. Methods: Animals received diets w ith or without 2.5-3% carbonyl iron for 6-9 weeks, followed by an etha nol-containing diet or a liquid control diet for 5-9 weeks. Desferriox amine was administered subcutaneously with mini-osmotic pumps. Alanine aminotransferase activity in serum and hepatic contents of glutathion e and malondialdehyde were determined. The hepatic level of cytochrome P450 2E1 was determined with Western Blotting using a specific polycl onal antibody. Results: The combination of iron and alcohol led to a m arked increase in serum alanine aminotransferase activity as compared with all other treatment groups, and iron chelation with desferrioxami ne reversed these increases. Treatment with alcohol alone led to sligh tly increased aminotransferases compared with controls. The level of c ytochrome P450 2E1 was significantly elevated in microsomes isolated f rom ethanol-treated rats, but neither additional iron supplementation nor desferrioxamine influenced this level significantly. Glutathione c ontents were increased in the livers of animals treated with iron and/ or ethanol. Malondialdehyde values were increased in iron-treated anim als, whereas neither ethanol nor desferrioxamine altered malondialdehy de levels significantly. Conclusions: The toxic effects exerted by the combination of iron overload and chronic ethanol feeding on rat liver are dependent on a pool of chelatable iron. The hepatic level of cyto chrome P450 2E1 is markedly induced by ethanol but not further altered by iron overload. Neither increased lipid peroxidation nor depletion of hepatic glutathione levels can explain the synergistic hepatotoxic effects of iron and ethanol in this model.