Acute Cyanide Toxicity, Complex IV, NO & Nitrite

急性氰化物毒性，复合物 IV，NO

• 批准号: 7684760
• 负责人: JAMES PETERSON
• 金额: $ 50.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684760
• 关键词: Acute; Cyanide; Toxicity; Complex; IV

DESCRIPTION (provided by applicant): The surprise use of either hydrogen cyanide gas (HCN) as a weapon directed against individuals deceived into becoming confined in enclosed spaces is likely to rapidly result in mass casualties. Nitric oxide (NO) is presently the only agent known that is able to displace cyanide (CN) from the active site of cytochrome c oxidase - the critical site of inhibition during acute intoxication. Enthusiasm for the use of traditional antidotes, nitrites (amyl and/or sodium nitrite), has decreased, in part, because of the uncertain assumption that its mechanism of action is the induction of methemoglobin (MetHb). Coincidently, extraordinary recent efforts have been redirected towards the role of nitrite in human physiology (as a source of NO). We now suggest that reversal of CN toxicity by nitrite is less dependent on production of MetHb but rather is secondary to formation of NO. Since nitrites and nitric oxide are already approved for human use and may provide an inexpensive antidote that is easy to administer (via inhalation) and can be readily stockpiled for public health use, we suggest that further understanding of their molecular mechanisms of action and a preclinical trial of their efficacy represent rational advances in chemical countermeasures. We propose that vaporized nitrite solution, to be administered by inhalation, will lead to the in situ production of NO which will ameliorate the acute toxic effects of CN. Our Specific Aims are to: 1) establish the biochemical mechanism through which NO counteracts the inhibition of isolated cytochrome c oxidase by HCN; 2) elucidate the mechanisms that account for the interactions between cytochrome c oxidase, HCN, molecular oxygen (O2) and NO, or sodium nitrite in mitochondria; 3) demonstrate in animals the efficacy, of NO and NO-releasing compounds, including sodium nitrite, in the treatment of acute cyanide intoxication.

描述(由申请人提供)： 出人意料地使用氰化氢气体(HCN)作为武器，对付受骗被限制在封闭空间中的个人，可能会迅速造成大规模伤亡。一氧化氮(NO)是目前已知的唯一一种能够将氰化物(CN)从细胞色素C氧化酶的活性部位取代的试剂，细胞色素C氧化酶是急性中毒时抑制作用的关键部位。对使用传统解毒剂亚硝酸盐(戊基和/或亚硝酸钠)的热情下降，部分原因是不确定的假设，即其作用机制是诱导高铁血红蛋白(MetHb)。巧合的是，最近的非凡努力被重新定向到亚硝酸盐在人类生理学中的作用(作为NO的来源)。我们现在认为，亚硝酸盐对CN毒性的逆转较少依赖于MetHb的产生，而是次要于NO的形成。由于亚硝酸盐和一氧化氮已经被批准用于人类，并可能提供一种廉价的解毒剂，易于(通过吸入)给药，并可随时储存用于公共卫生用途，我们建议进一步了解它们的分子作用机制，并对其有效性进行临床前试验，这是化学对策方面的合理进展。我们认为，雾化吸入亚硝酸盐溶液将导致NO的原位产生，从而减轻CN的急性毒性效应。我们的具体目标是：1)建立NO中和HCN对细胞色素C氧化酶的抑制的生化机制；2)阐明细胞色素C氧化酶、HCN、分子氧(O2)与线粒体中NO或亚硝酸钠相互作用的机制；3)在动物身上证明NO和NO释放化合物，包括亚硝酸钠，在治疗急性氰化物中毒中的有效性。