An Approach toward Antidotes for Phosphine

磷化氢解毒剂的研究方法

• 批准号: 9418908
• 负责人: LINDA L PEARCE
• 金额: $ 23.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9418908
• 关键词: Acids; Acute; Address; Affinity; Aluminum; Animals; Antidotes; Binding; Binding Sites; Biochemical; Blood; Blood Circulation; Blood Vessels; Blood specimen; Breathing; Cessation of life; Classification; Cobalt; Complex; Cyanides; Development; Diffuse; Dose; Effectiveness; Electron Transport; Enzyme Inhibition; Enzymes; Erythrocytes; Excision; Exhalation; Future; Gases; Gold; Heart; Heart Rate; Heme Iron; Heme aa3 Cytochrome Oxidase; Hemoglobin; Hemolysis; Human; Hypotension; Intoxication; Intraperitoneal Injections; Ions; Legal; Lethal Dose 50; Ligands; Liquid substance; Lower Organism; Metals; Methemoglobinemia; Mitochondria; Modification; Molecular Target; Monitor; Mus; Nitric Oxide Synthase; Oxidation-Reduction; Phosphines; Poison; Poisoning; Pulse Oximetry; Reaction; Reactive Oxygen Species; Reporting; Rodenticides; Sodium Nitrite; Structure; Sulfides; Symptoms; Synthesis Chemistry; Testing; Toxic effect; Uncertainty; Water; Work; Zinc; acute toxicity; beef; complex IV; cytochrome c oxidase; design; experimental study; in vivo; mitochondrial membrane; protocol development; response; therapeutic development; toxicant; vapor; weapons

An Approach Toward Antidotes for Phosphine More human poisonings (both accidental and deliberate) are reported worldwide due to phosphine than any other toxic substance. Aluminum and zinc phosphides are legally available from many commercial outlets in pelleted forms for use as rodenticides in the U.S. When these pellets come into contact with water (liquid/vapor) they release phosphine gas and could easily be deployed as weapons. A key target for phosphine is widely believed to be the electron transport chain of mitochondria, but there appears to be adearth of information concerning its toxic mode of action at the biochemical and cellular levels. We proposeto better identify the molecular target(s) of phosphine to facilitate future development of agents to reverse the acute toxicity. Also, since phosphine is a good ligand species, but a relatively slow acting poison mainly eliminated through exhalation, we suggest that a decorporating approach using metal ion complexes must be appropriate for ameliorating phosphine poisoning. The cobalt-containing water-soluble macrocyclic complexes we have recently shown to be effective antidotes to cyanide [Benz et al (2012) Chem. Res. Tox., 25, 2678-86; Ibid (2016)] and sulfide [Cronican et al (2015) Chem. Res. Tox., 28, 1398-1408] in mice are not antidotal toward phosphine. We hypothesize that compounds containing gold(I) will prove to be good candidate antidotes and be non-toxic at the levels required to be efficacious in treating phosphine intoxication. Aim 1. To demonstrate that while phosphine can indeed act as a mitochondrial poison through inhibition of the electron- transport chain at cytochrome c oxidase in mitochondria, that this is of less toxic consequence in vivo than damage to hemoglobin/erythrocytes. Aim 2. To determine if some easily prepared univalent gold complexes antidotal toward phosphine in mice.

磷化氢解毒剂的研究 全球范围内报告的人类中毒事件（包括意外和故意）更多， 比任何其他有毒物质。磷化铝和磷化锌是合法的 从许多商业渠道以丸状形式在美国用作杀鼠剂。 颗粒与水（液体/蒸汽）接触，它们释放出磷化氢气体， 作为武器使用。膦的一个关键目标被广泛认为是电子传输 链的线粒体，但似乎是缺乏有关其毒性模式的信息 在生物化学和细胞水平上的作用。我们建议更好地识别 膦的靶点，以促进未来开发逆转急性毒性的药剂。还有， 由于膦是良好的配体物质，但主要消除了相对缓慢作用的毒物 通过呼气，我们建议使用金属离子络合物的去离子方法必须 适用于改善磷化氢中毒。含钴水溶性 大环配合物，我们最近已经证明是有效的解毒氰化物[奔驰等人 （2012）化学研究毒理学，25，2678-86;同上（2016）]和硫化物[Cronican等人（2015）Chem. Res. 毒性测试，28，1398-1408]对磷化氢没有解毒作用。我们假设 含金（I）的化合物将被证明是良好的候选解毒剂，并且在20 ℃时无毒。 有效治疗磷化氢中毒所需的水平。目标1。证明 虽然磷化氢确实可以通过抑制电子- 线粒体中细胞色素c氧化酶的转运链，这对 比对血红蛋白/红细胞的损害更大。目标二。为了确定一些容易准备的 单价金络合物对小鼠体内磷化氢的解毒作用。