Effect of iron overload on spontaneous and xenobiotic-induced lipid peroxidation in vivo

To study the effect of iron-overload on hepatic lipid peroxidation, two rat models of haemochromatosis were employed: in the first model resembling secondary haemochromatosis, repeated i.p. injections with Fe-dextran led to an accumulation of Fe in Kupffer cells, while in the second model resembling hereditary haemochromatosis, iron was located mainly in periportal hepatocytes after feeding on a diet containing 3.5% Fe-fumarate for 3 weeks. In both models, total hepatic iron content was elevated four- to fivefold over controls. In vivo lipid peroxidation (ethane exhalation) was enhanced only in the second model, indicating that the hepatocytes are the main targets of Fe-induced lipid peroxidation. Low hepatotoxicity was observed in the second model. Additional treatment of the rats with hepatotoxic agents led to different results: with ethanol and bromobenzene, lipid peroxidation was only evident in both models of iron-overload, while paracetamol-induced lipid peroxidation was seen only in Fe-fumarate-fed rats. CCl4-induced lipid peroxidation was strongly enhanced in both models of haemochromatosis. Hepatotoxicity was enhanced by iron overload only in the case of CCl4-treated, Fe-fumarate-fed rats. The activities of phase I and phase II enzymes of xenobiotic metabolism were not markedly altered in livers of iron-overloaded rats. This implies that neither the bioactivation nor the detoxification of the agents studied were affected in experimental haemochromatosis.