Second only to the blood-forming marrow in its traffic of iron, the liver is of unique importance as an organ where this essential metal is taken up from iron-binding proteins, stored, utilized for the synthesis of iron- dependent enzymes, recycled from senescent and damaged red blood cells, and excreted via the bile. Moreover, the liver is a major target of iron toxicity in acute and chronic iron overload, and may also sustain injury in severe iron deficiency. Virtually all aspects of iron metabolism may be studied in this complex organ. Our approach is to seek deeper understanding of iron metabolism at cellular and molecular levels by examining iron transport, processing, storage and toxicity in isolated liver cells, Of continuing interest is the interaction of transferrin erythroid cells. The contributions of receptor- mediated nad receptor-independent events, and of membrane redox processes, in the uptake of iron from transferrin by hepatocytes will be investigated by thermodynamic, kinetic and EPR spectroscopic erythrophagocytosing Kupffer cells, deals with ferritin as an iron source for hepatocytes. Because of its large iron-accommodating capacity, ferritin may provide iron to hepatocytes, in specific receptor-dependent fashion, at 50 times the rate given by transferrin. We will determine whether iron uptake from ferritin is regulated by cellular iron status, as we examine the fate of exogenous ferritin and its iron in the hepatocyte. To assist in this work, preparation of monoclonal antibodies to the ferritin receptor will be undertaken. Finally, we will pursue studies of erythrophagocytosing Kupffer cells, with a goal of determining whether acute iron toxicity underlies the lethal effects of unrestrained red cell ingestion. In testing this hypothesis, we will correlate studies based on spin trapping of oxygen-derived radicals, chemical detection of lipid peroxidation, potentiation of killing by ascorbate and protective effects of scavengers of iron and noxious oxygen species. Our conviction is that these investigations will contribute in managing disorders of iron metabolism - among the most common and most disabling of humankind's ills.
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