Discovering novel metabolic targets to mitigate cyanide toxicity

总结 氰化物基本上是一种代谢毒素。虽然它有许多已知的目标， 其病理后果可归因于抑制线粒体 通过电子传递链的复合物IV的失活来呼吸。鉴于这种 代谢在氰化物中毒的病理生理学中的重要作用，我们期望 代谢调节剂有可能作为治疗对策。在 事实上，该中心最近发现，代谢物乙醛酸深刻 减轻斑马鱼、小鼠和兔子的氰化物致死性。我们建议以此为基础， 通过定义这种和其他试剂的代谢功能，并测试 氧化还原失衡是氰化物毒性的基础。我们进一步发现 TCA循环的活化剂和底物也赋予抗氰化物性， 建议进一步开发这种药物作为治疗剂，并完成我们的高度 代谢物和代谢调节剂的集中筛选。我们还提出了一系列 机械实验，以询问复合物IV抑制的程度， 氰化物毒性的机制和介导毒性的器官。这些研究 将与旨在了解代谢生理学的实验协同作用， 氰化物毒性和对各种缓解方法的反应。我们假设 更深入地了解氰化物毒性和缓解的代谢基础， 为采取合理的反措施及其适当应用提供了信息。

Summary Cyanide is fundamentally a metabolic toxin. Although it has many known targets, many of its pathological consequences can be ascribed to inhibition of mitochondrial respiration through inactivation of Complex IV of the electron transport chain. Given this prominent role of metabolism in the pathophysiology of cyanide poisoning, we expect that modulators of metabolism might have potential as therapeutic countermeasures. In fact, this Center has recently discovered that the metabolite glyoxylate profoundly mitigates cyanide lethality in zebrafish, mice and rabbits. We propose to build upon this foundation by defining the metabolic functions of this and other agents and testing the hypothesis that redox imbalance underlies cyanide toxicity. We have further discovered that activators and substrates of the TCA cycle also confer cyanide resistance and propose to further develop such agents as therapeutics as well as complete our highly focused screen of metabolites and metabolic modulators. We also propose a series of mechanistic experiments to interrogate the extent to which Complex IV inhibition is the mechanism of cyanide toxicity and the organs that mediate that toxicity. These studies will synergize with experiments aimed at understanding the metabolic physiology of cyanide toxicity and the response to various mitigating approaches. We hypothesize that a deeper understanding of the metabolic basis of cyanide toxicity and mitigation will inform a rational approach to countermeasures and their appropriate application.