ARSINE METABOLISM AND MECHANISM OF TOXICITY

胂的代谢和毒性机制

• 批准号: 2155448
• 负责人: DEAN E CARTER
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-15 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2155448
• 关键词: antidotes; arsenic; atomic absorption spectrometry; cytotoxicity; drug design /synthesis /production; electron spin resonance spectroscopy; environmental toxicology; erythrocytes; free radical oxygen; gas chromatography mass spectrometry; hemoglobin; hemolysis; laboratory rat; nuclear magnetic resonance spectroscopy; occupational hazard; oxidative stress; scintillation counter; toxicant interaction; toxin metabolism

Arsine is an important toxicant which has received little study despite its extensive use in the semiconductor industry. In addition to its industrial use, it can be formed when acid or base contracts inorganic arsenic and elemental metals like aluminum, tin, zinc and others. Thus, we predict that it can be formed in the environment in such places as hazardous waste dumpsites. The major route of toxicity for arsine is massive hemolysis. Arsine exposure ia a serious problem because there is no treatment except total blood exchange. Thus, a large scale accident would deplete the blood reserves of even the largest of blood banks. It is surprising that arsine has not received more attention because it is in widespread use and there is no good treatment after exposure. This proposal will study the mechanism of arsine-based hemolysis and characterize the changes which occur in the arsine molecule as a means to eventually design an effective treatment. The primary hypothesis is that arsine binds hemoglobin as first step and then reacts to form an oxidized arsine product and active oxygen species. Active oxygen species then go on to react with cellular components to cause hemolysis in a manner similar to other hemolytic agents. A second hypothesis is also considered in which hemoglobin reacts in a similar manner to P-450 and forms a reactive arsine metabolite which then could attack important cellular constituents. The studies proposed here combine a chemical approach using nuclear magnetic resonance and electron spin resonance spectroscopy to characterize the arsine-hemoglobin interaction with biological studies which characterize the oxidant stress on the red blood cell. Other aims include the characterization of the arsine species formed and an examination of the role of oxygen saturation on hemolysis. Our objective is to use these results to design a rational treatment for arsine toxicity.

砷是一种重要的毒物，研究甚少。 尽管它在半导体行业中被广泛使用。此外 对于工业用途，它可以在酸或碱收缩时形成 无机砷和元素金属，如铝、锡、锌和 其他。因此，我们预测它可以在#年的环境中形成。 危险废物堆放场等场所。 砷的主要毒性途径是大量溶血。砷化氢 暴露是一个严重的问题，因为除了 全血交换。因此，一场大规模的事故将耗尽 即使是最大的血库也有血液储备。 令人惊讶的是，砷没有得到更多的关注，因为 它被广泛使用，暴露后没有良好的治疗方法。 该方案将研究以砷为基础的溶血和 描述在砷分子中发生的变化，作为一种手段 最终设计出一种有效的治疗方法。主要假设 砷是第一步与血红蛋白结合，然后反应形成 一种氧化的砷产物和活性氧物种。活性氧 然后物种继续与细胞成分发生反应，从而导致 类似于其他溶血剂的溶血作用。一秒钟 还考虑了一种假设，在这种假设中，血红蛋白在类似的 途径P-450，并形成一种反应性砷代谢物，然后 可以攻击重要的细胞成分。 这里提出的研究结合了一种使用核能的化学方法 磁共振和电子自旋共振光谱分析 用生物学研究表征砷与血红蛋白的相互作用 这是红血球氧化压力的特征。其他 目标包括所形成的砷物种的表征和 血氧饱和度对溶血作用的检测。我们的 目的是利用这些结果设计一种合理的治疗方法 砷化氢中毒。