An Approach toward Antidotes for Phosphine

磷化氢解毒剂的研究方法

基本信息

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
项目类别：
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

项目摘要

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方法由于以下原因，世界范围内报告了更多的人类中毒（意外和故意）磷化氢比任何其他有毒物质都重要。磷化铝和磷化锌是合法可用的在美国，来自许多商业渠道的颗粒形式用作灭鼠剂。颗粒与水（液体/蒸汽）接触时会释放磷化氢气体，并且很容易被部署为武器。人们普遍认为磷化氢的一个关键目标是电子传输线粒体链，但似乎缺乏有关其毒性模式的信息生化和细胞水平上的作用。我们建议更好地识别分子磷化氢的目标，以促进未来开发逆转急性毒性的药物。还，因为磷化氢是一种良好的配体物种，但作用相对缓慢的毒物主要被消除通过呼气，我们建议使用金属离子络合物的装饰方法必须是适用于缓解磷化氢中毒。含钴水溶性我们最近证明大环配合物是氰化物的有效解毒剂[Benz等人 (2012)化学。资源。毒理学，25，2678-86；同上 (2016)] 和硫化物 [Croncan et al (2015) Chem.资源。 Tox., 28, 1398-1408] 在小鼠中对磷化氢没有解毒作用。我们假设含有金（I）的化合物将被证明是良好的候选解毒剂，并且在有效治疗磷化氢中毒所需的水平。目标 1. 证明而磷化氢确实可以通过抑制电子来充当线粒体毒物线粒体中细胞色素 C 氧化酶的转运链，这对细胞色素 C 氧化酶的毒性较小体内比对血红蛋白/红细胞的损害更大。目标 2. 确定是否有一些容易准备的单价金络合物对小鼠磷化氢具有解毒作用。