ROLE OF IRON IN TOXICITIES AND PATHOLOGIES

铁在毒性和病理学中的作用

• 批准号: 3253293
• 负责人: STEVEN D. AUST
• 金额: $ 12.12万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253293
• 关键词: SDS polyacrylamide gel electrophoresis; antioxidants; autoradiography; density gradient ultracentrifugation; enzyme activity; enzyme linked immunosorbent assay; exopeptidase; ferritin; ferroxidase; free radical oxygen; gel filtration chromatography; iron; laboratory rat; metal complex; oxidation; pathology; peroxidation; polymerase chain reaction; superoxides; toxicology; western blottings

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.

这个建议是继续研究我们的建议，铁参与 在某些毒性和病理学中。 我们建议铁 贮存蛋白铁蛋白可能是这种铁的来源。 超氧化物和 特别是有机自由基，从铁蛋白中释放铁。 这个钢铁意志 催化组织的氧化，包括脂质过氧化。 我们提出 这可能是一种机制，通过这种机制， 有毒 我们还提出，铁蛋白可能是一种保护性蛋白质， 将铁置于铁蛋白中的有效方法。 我们建议 血浆铜蓝蛋白可以实现这一点，因为它是一种有效的铁氧化酶， 不释放部分还原的氧物质如氢 过氧化物 因此，铁蛋白和血浆铜蓝蛋白的组合可具有 抗氧化活性 越来越多的证据表明，铜蓝蛋白是一种 重要细胞内、肝外酶。 我们建议进一步 调查这个假设。 我们也会调查 铁蛋白和铜蓝蛋白都可能是由氧化还原循环诱导的 毒素 我们还必须进一步研究铁蛋白，因为我们发现， 它对百草枯和阿霉素释放铁的敏感性不同 这取决于它所分离的组织。 我们建议 测试这是由于重质与轻质含量不同的假设 肽链 我们还建议测试假设，一些复杂的 可能存在于铁蛋白和铜蓝蛋白之间。 最后，我们建议 将我们的研究扩展到研究已经被提出具有 “氧化酶”活性。 我们将从γ-谷氨酰酶开始 转肽酶 我们认为酶的产物 通常测定的是良好的铁还原剂， 这种铁是与此相关的“氧化酶”活性的来源。 酵素 这种铁通常在生理条件下得到很好的控制 因此γ-谷氨酰转肽酶的“氧化酶”活性可能不是 除了在不寻常的情况下。