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IRON AND TOXICITES AND PATHOLOGIES

铁与毒性和病理学

基本信息

批准号：
2518628
负责人：
STEVEN D. AUST
金额：
$ 18.85万
依托单位：
UTAH STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-05-01 至 1999-08-31
项目状态：
已结题

项目摘要

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.

这是一项继续我们对铁在各种疾病中作用的研究的建议毒性和病理性。铁非常活泼，能够氧化。通过产生羟基直接或间接地产生生物分子 Fenton反应产生的自由基(OH)(Fe+H202生成Fe111+0H+OH-)。铁可以从铁储存蛋白铁蛋白中释放出来由NADPH-细胞色素还原酶产生的各种毒素的自由基形式，以及超氧化物，这可能是氧化还原循环中的毒素造成的。免费化学物质的单电子氧化也可以产生自由基。通过过氧化物酶。我们认为这些酶(过氧化物酶)和各种其他化学物质也可以从铁蛋白中释放铁。我们最近做了发现02也是由各种不同的H202氧化产生的由过氧化物酶产生的自由基。因此，我们建议调查通过已知的过氧化物酶和毒素从铁蛋白中释放铁过氧化物酶的底物(即对苯二酚，氯丙嗪，苯妥英、二和三甲二酮、氨基三唑、四甲基联苯胺、等)。我们还将研究氧气在铁释放过程中的作用通过这些化学物质和酶从铁蛋白中分离出来。另一方面，铁蛋白可能对铁的毒性作用有保护作用，如果有将铁放入铁蛋白的有效机制。我们不相信铁蛋白有其自身的载铁能力。我们建议这是铜蓝蛋白的作用。然而，我们必须证明铜蓝蛋白是一种组织酶，它与铁蛋白结合以有效地装载把铁加入铁蛋白中。我们还将演示铜蓝蛋白和铁蛋白对铁催化的脂质过氧化具有保护作用上述释放机制，特别是在存在各种不同的可以与铁复合的生物分子。我们还建议确定是否几种可能螯合铁的抗氧化剂可以抑制过氧化物酶。和铁蛋白依赖的脂质过氧化。