We propose that iron catalyzes the free radical oxidation of biomolecules that results in the toxicity of redox cycling chemicals, irradiation damage and iron overload. The iron that catalyzes these toxicities or pathologies must be a low molecular weight chelate of iron which normally exists in very low concentration or otherwise does not catalyze the oxidation of tissue macromolecules. Upon iron overload or the exposure to chemicals or conditions which promote the release of iron from ferritin, the released iron has the potential to be toxic. We hypothesize that this toxicity may be at least minimized by ceruloplasmin catalyzed oxidation and sequestration of the iron in ferritin. The long-term objective of the proposed research is to study ferritin and ceruloplasmin with regards to their ability to sequester iron in order to devise an effective therapeutic system. We propose to determine if a number of redox cycling chemicals or irradiation cause the release of iron from ferritin in vivo in a number of tissues, and to determine if ceruloplasmin and ferritin might provide protection against the toxicity of this iron. We propose to study paraquat, diquat, carbon tetrachloride, adriamycin, alloxan and Y-irradiation in their respective target tissues. We propose to study the interactions between ceruloplasmin and serum ferritin, three isoferritins, and the recently described lipid-associated ferritin.
| Miller, D M; Grover, T A; Nayini, N et al. (1993) Xanthine oxidase- and iron-dependent lipid peroxidation. Arch Biochem Biophys 301:1-7 |
| de Silva, D M; Aust, S D (1993) Ferritin and ceruloplasmin in oxidative damage: review and recent findings. Can J Physiol Pharmacol 71:715-20 |
| de Silva, D; Guo, J H; Aust, S D (1993) Relationship between iron and phosphate in mammalian ferritins. Arch Biochem Biophys 303:451-5 |
| Ryan, T P; Miller, D M; Aust, S D (1993) The role of metals in the enzymatic and nonenzymatic oxidation of epinephrine. J Biochem Toxicol 8:33-9 |
| Barr, D P; Aust, S D (1993) On the mechanism of peroxidase-catalyzed oxygen production. Arch Biochem Biophys 303:377-82 |
| Ryan, T P; Grover, T A; Aust, S D (1992) Rat ceruloplasmin: resistance to proteolysis and kinetic comparison with human ceruloplasmin. Arch Biochem Biophys 293:1-8 |
| de Silva, D; Aust, S D (1992) Stoichiometry of Fe(II) oxidation during ceruloplasmin-catalyzed loading of ferritin. Arch Biochem Biophys 298:259-64 |
| de Silva, D; Miller, D M; Reif, D W et al. (1992) In vitro loading of apoferritin. Arch Biochem Biophys 293:409-15 |
| Ryan, T P; Aust, S D (1992) The role of iron in oxygen-mediated toxicities. Crit Rev Toxicol 22:119-41 |
| Minotti, G; Aust, S D (1992) Redox cycling of iron and lipid peroxidation. Lipids 27:219-26 |
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