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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK037927-04
Application #
3236955
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1987-01-01
Project End
1994-12-31
Budget Start
1990-01-15
Budget End
1990-12-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Thorstensen, K; Trinder, D; Zak, O et al. (1995) Uptake of iron from N-terminal half-transferrin by isolated rat hepatocytes. Evidence of transferrin-receptor-independent iron uptake. Eur J Biochem 232:129-33
Zak, O; Trinder, D; Aisen, P (1994) Primary receptor-recognition site of human transferrin is in the C-terminal lobe. J Biol Chem 269:7110-4
Black, S M; Harikrishna, J A; Szklarz, G D et al. (1994) The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, cytochrome P450scc. Proc Natl Acad Sci U S A 91:7247-51
Sasaki, K; Zak, O; Aisen, P (1993) Antisense suppression of transferrin receptor gene expression in a human hepatoma cell (HuH-7) line. Am J Hematol 42:74-80
Egan, T J; Zak, O; Aisen, P (1993) The anion requirement for iron release from transferrin is preserved in the receptor-transferrin complex. Biochemistry 32:8162-7
Egan, T J; Barthakur, S R; Aisen, P (1992) Catalysis of the Haber-Weiss reaction by iron-diethylenetriaminepentaacetate. J Inorg Biochem 48:241-9
Aisen, P (1991) Ferritin receptors and the role of ferritin in iron transport. Targeted Diagn Ther 4:339-54
Thorstensen, K; Aisen, P (1990) Release of iron from diferric transferrin in the presence of rat liver plasma membranes: no evidence of a plasma membrane diferric transferrin reductase. Biochim Biophys Acta 1052:29-35
Sibille, J C; Ciriolo, M; Kondo, H et al. (1989) Subcellular localization of ferritin and iron taken up by rat hepatocytes. Biochem J 262:685-8

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