The experiments described in this research proposal will povide new information about the pathophysiologic mechanisms whereby chronic iron overload causes hepatic injury and fibrosis. These observations will cintribute to our understanding of 1) the development of chronic liver disease in patients with both primary and the many forms of secondary hemochromatosis, 2) the role of iron-induced lipid peroxidation as the primary cause of organelle and cellular dysfunction in chronic iron overload and 3) mechanisms of hpatotoxicity in general. Using a newly established model of experimental iron overload, we will determine if treatment with iron chelating drugs will inhibit the hepatotoxic manifestations which we have previously observed in rats with chronic iron overload. We will evaluate the effects of chronic iron overload on hepatic vitamin E metabolism to determine whether vitamin E deficiency acts synergistically in producing the hepatotoxicity of iron overload or if vitamin E supplementation may be protective. Studies of hepatic glutathione metabolism will be performed to determine if there is an increase in hepatic turnover of glutathione in chronic iron overload or if the specific reduction of cellular reduced gluthathione can result in increased hepatotoxicity. These studies (chelating drugs, vitamin E and glutathione metabolism) will provide important information about the role of iron-induces, free radical-mediated peroxidative injury to hepatic organelles as a primary pathophysiologic event and may have important implications for minimizing tissue damage in human iron overload states. Experiments in which ethanol is chronically administered in conjunction with iron overload will provide informatin about the role of iron as a cofactor in other identifiable cytotoxic pathways. Finally, having achieved iron-induced hepatic fibrosis in our new model of iron overload we will now be able to perform detailed studies of several biochemical parameters of collagen metabolism in chronic severe iron overload. These studies will be done in conjunction with administration of iron chelating drugs, manipulation of cytoprotective mechanisms and with coadministration of ethanol to determine the effects of iron-induced fibrogenesis. Our proposed experiments will explore the complex interrelationships of iron excess with endogenous cytoprotective mechanisms and exogenous heptotoxins, thus providing new insights into the pathophysiologic mechanisms of liver damage in iron overload.
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