IRON AND TOXICITIES AND PATHOLOGIES

铁与毒性和病理学

• 批准号: 2153930
• 负责人: STEVEN D. AUST
• 金额: $ 12.96万
• 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/2153930
• 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.

该建议是继续研究我们涉及铁的提议 在某些毒性和病理中。 我们提出了铁 储存蛋白铁蛋白可能是该铁的来源。 超氧化物，和 特别是有机自由基，从铁蛋白释放铁。 这铁意志 催化组织的氧化，包括脂质过氧化。 我们建议 这可能是一种机制，氧化还原周期可能是一种机制 有毒的。 我们还建议铁蛋白可能是一种保护蛋白 将铁放入铁蛋白的有效方法。 我们提出了这一点 Ceruloplasmin可以做到这一点，因为它是一种有效的铁氧化酶 不会释放部分还原的氧气，例如氢 过氧化物。 因此，铁蛋白和ceruloplasmin的组合可能具有 抗氧化活性。 有证据表明ceruloplasmin是 重要的细胞内肝外酶。 我们建议进一步 研究这一假设。 我们还将调查提案 氧化还原循环可以诱导铁蛋白和谷蛋白 毒素。 我们还必须进一步研究铁蛋白，因为我们发现 在帕拉奎特和阿霉素的易感性释放方面有所不同 取决于分离的组织。 我们正在提议 检验以下假设，即这是由于重量与光的不同含量引起的 肽链。 我们还建议检验某些复杂的假设 铁蛋白和谷蛋白酶素之间可能存在。 最后，我们建议 扩展我们的研究以调查已提议具有的酶 “氧化酶”活性。 我们将从酶γ-谷氨酰基开始 转肽酶。 我们建议酶的产物是 通常测定的是良好的铁还原剂，随后的氧化 该铁是与此相关的“氧化酶”活性的来源 酶。 这种铁通常在生理条件下得到很好的控制 因此，γ-谷氨基转肽酶的“氧化酶”活性可能不是 除非异常情况，否则生理意义。