This is a proposal to continue our research on the role of iron in various toxicities and pathologies. Iron is very reactive, able to oxidize biomolecules directly or indirectly by the generation of the hydroxyl radical (OH) by Fenton reaction (Fe + H202 yielding Fe111 + 0H + OH-). Iron can be released from the iron storage protein ferritin by the free radical form of various toxins, generated by NADPH-cytochrome reductase, and superoxide, which can result from toxins that redox cycle. Free radicals can also be produced by the one-electron oxidation of chemicals by peroxidases. We propose that these enzymes (peroxidases) and various other chemicals can also release iron from ferritin. We have recently discovered that 02 is also produced by the oxidation of H202 by various radicals produced by peroxidases. We therefore propose to investigate the release of iron from ferritin by peroxidases and toxins that are known to be substrates for peroxidases (i.e., hydroquinones, chlorpromazine, phenytoin, di- and trimethadione, aminotriazole, tetramethylbenzidine, etc.). We will also investigate the role of O2 in the release of iron from ferritin by these chemicals and enzymes. On the other hand, ferritin may be protective against the toxic effects of iron if there is an efficient mechanism for placing the iron into ferritin. We don't believe that ferritin has its own iron loading ability. We propose that this is the role of ceruloplasmin. However, we must show that ceruloplasmin is a tissue enzyme and that it associates with ferritin to efficiently load iron into the ferritin. We will also demonstrate that ceruloplasmin and ferritin are protective against iron-catalyzed lipid peroxidation by the release mechanisms noted above, especially in the presence of various biomolecules that can complex with iron. We also propose to determine if several proposed antioxidants that may chelate iron can inhibit peroxidase and ferritin-dependent lipid peroxidation.
| 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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