Discovering novel metabolic targets to mitigate cyanide toxicity

摘要 氰化物基本上是一种新陈代谢毒素。尽管它有许多已知的目标，但许多 其病理后果的一部分可归因于线粒体的抑制 通过使电子传递链的复合体IV失活而引起的呼吸作用。鉴于此， 代谢在氰化物中毒的病理生理中的重要作用，我们期待 新陈代谢调节剂可能具有治疗对策的潜力。在……里面 事实上，该中心最近发现代谢物乙醛深刻地 减轻氰化物对斑马鱼、小鼠和兔子的致命性。我们建议在此基础上再接再厉 通过定义该制剂和其他制剂的代谢功能并测试 假设氧化还原失衡是氰化物毒性的基础。我们进一步发现 TCA循环的激活剂和底物也赋予了抗氰化物和 建议进一步开发治疗学等药物，并完成我们的高度 代谢物和代谢调节剂的重点筛选。我们还提出了一系列 询问复合体IV抑制的程度的机械实验 氰化物毒性的机制和调节这种毒性的器官。这些研究 将与旨在了解人体代谢生理学的实验协同工作 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将 告知采取应对措施的合理方法及其适当应用。

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.