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.

这是一项提议，旨在继续我们研究铁在各种中的作用毒性和病理。铁非常反应性，能够氧化直接或间接地通过羟基生成生物分子 Fenton反应（Fe + H202产生Fe111 + 0H + OH-）的自由基（OH）。铁可以通过免费的铁储存蛋白铁蛋白释放各种毒素的激进形式，由NADPH-CytoChrome还原酶产生，和超氧化物，这可能是由氧化还原周期的毒素引起的。自由的自由基也可以通过化学物质的单电子氧化产生通过过氧化物酶。我们建议这些酶（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。我们最近有发现02也是通过各种H202氧化产生的过氧化物酶产生的自由基。因此，我们建议调查通过过氧化物酶和毒素从铁蛋白中释放出铁的铁是过氧化物酶的底物（即羟基酮，氯丙嗪，苯妥英钠，二甲二世，氨基三唑，四甲基苯胺， ETC。）。我们还将研究O2在铁释放中的作用这些化学物质和酶从铁蛋白。另一方面，铁蛋白如果有一个将铁置于铁蛋白中的有效机制。我们不相信该铁蛋白具有自己的铁载能力。我们建议这是 Ceruloplasmin的作用。但是，我们必须证明ceruloplasmin是组织酶及其与铁蛋白相关以有效加载熨烫进入铁蛋白。我们还将证明Ceruloplasmin和铁蛋白可防止催化铁催化的脂质过氧化上面指出的释放机制，尤其是在存在各种的情况下可以与铁复合的生物分子。我们还建议确定是否可能螯合铁可以抑制过氧化物酶的几种提出的抗氧化剂和铁蛋白依赖性脂质过氧化。