This proposal is to continue research on our proposal that iron is involved in certain toxicities and pathologies. We have proposed that the iron storage protein ferritin may be the source of this iron. Superoxide, and especially organic radicals, release iron from ferritin. This iron will catalyze the oxidation of tissues including lipid peroxidation. We propose that this may be a mechanism by which chemicals that redox cycle may be toxic. We also propose that ferritin may be a protective protein given an efficient method to place the iron into ferritin. We propose that ceruloplasmin may accomplish this as it is an effective ferroxidase which does not release partially reduced species of oxygen such as hydrogen peroxide. Thus, a combination of ferritin and ceruloplasmin may have antioxidant activity. Evidence is mounting that ceruloplasmin is an important intracellular, extrahepatic enzyme. We propose to further investigate this hypothesis. We are also going to investigate the proposal that both ferritin and ceruloplasmin may be induced by redox cycling toxins. We also have to further investigate ferritin as we have found that it differs in susceptibility to iron release by paraquat and adriamycin depending upon the tissue from which it was isolated. We are proposing to test the hypothesis that this is due to different content of heavy vs light peptide chains. We also propose to test the hypothesis that some complex may exist between ferritin and ceruloplasmin. Finally, we propose to extend our research to investigate enzymes that have been proposed to have """"""""oxidase"""""""" activity. We will start with the enzyme gamma-glutamyl transpeptidase. We propose that the products of the enzyme as it is usually assayed are good iron reductants and that subsequent oxidation of this iron is the source of the """"""""oxidase"""""""" activity associated with this enzyme. This iron is usually well controlled in physiological conditions so the """"""""oxidase"""""""" activity of gamma-glutamyl transpeptidase is probably not of physiological significance except in unusual situations.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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Utah State University
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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
Miller, D M; Grover, T A; Nayini, N et al. (1993) Xanthine oxidase- and iron-dependent lipid peroxidation. Arch Biochem Biophys 301:1-7
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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