EFFECTS OF ALCOHOL ON IRON HOMEOSTASIS

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Alcoholism and alcohol liver disease (ALD) are associated with disorders of iron metabolism ranging from iron deficiency anemia to hemochromatosis and siderosis. As the liver is not only the main site of iron storage, but also secretes the major iron transport protein, transferrin, it seems likely that there is an association between the effects of alcohol on liver cells and iron homeostasis, either as a direct result of toxicity, or through some secondary mechanism of modulation. It is the aim of this study, therefore, to investigate the relationships between alcohol, iron (and various transport and storage proteins), and the various liver cell populations, in particular hepatocytes and Kupffer cells. This project focuses on examination of the system in vitro, utilizing specific populations of cells isolated enzymatically from livers of normal and treated animals (rats). The two rat serum isotransferrins will be purified and radiolabelled with iron and iodine and test systems involving suspensions of viable liver cell populations will be set up and validated, in order to study the interactions among iron, transferrin and the various liver cells. Information obtained from these initial suspensions will be used as a basis for more extensive investigations with cell cultures. In addition to the use of cultured cells in the presence of ethanol, the system will be perturbed through alterations in iron availability, changes in the media constituents and by the addition of endotoxins. The possible cell:cell interactions will also be tested by using "conditioned media" from one cell population to influence specific aspects of iron metabolism in other types of cells, or by direct co-culture with two or more cell populations. It is anticipated that extrapolation to the human disease state will be greatly facilitated by these studies and that this will lead to a better understanding of the disturbances of iron metabolism that occurs in alcoholic liver disease, i.e., iron overload and anemia.