ACUTE ACRYLONITRILE INTOXICATION--ANTIDOTAL ASSESSMENT

丙烯腈（AN）是一种广泛用于生产丙烯腈的化学品。 合成纤维、塑料和橡胶。 AN是一种反应性化学品， 实验动物的急性致死作用。 人类死亡 意外暴露于硝酸铵的案例 当前工业 卫生习惯可以限制工人在正常工作期间接触AN， 职业程序。 然而，意外暴露于高水平 会严重影响参与生产的个人的健康， 运输和AN的最终用途。 在发生重大意外事故时， 即使是普通民众的健康也可能受到影响。 影响。AN可氧化代谢为氰化物， 比母体分子的毒性大一倍 然而，在这方面， 由于它与体内的巯基具有高化学反应性， 母体AN分子也被认为是有毒的。 因此，AN是一把双刃剑，必须采取解毒措施， 考虑到氰化物成分和其“其他”成分， 毒性作用。 不幸的是，目前推荐的解毒剂 AN中毒的治疗仅侧重于氰化物的管理 中毒 我们的目标是模拟急性皮肤AN暴露， 为了测量含巯基的解毒剂，例如N-乙酰基-L- 半胱氨酸，以增加丙烯腈从 流通 这将最大限度地减少AN的可用时间， 在体内与蛋白质巯基发生化学反应。 此外，我们建议 为了确定N-乙酰-L-半胱氨酸是否能够降低 共价结合，可能通过增加AN清除率，是直接的 N-乙酰-L-半胱氨酸的作用，或通过 作为谷胱甘肽的前体。此外，我们计划使用一个 和二维凝胶电泳来分离特定组织 AN共价结合的蛋白质，并使用N-末端 对印迹凝胶进行测序以鉴定这些蛋白质。 的能力 含巯基的解毒剂，以保护这些蛋白质免受AN共价 将测量结合力。 最后，我们计划使用AN代谢产物 排泄模式和AN对特定氨基酸位点的标记 在血红蛋白中，作为AN处置变化的生物标志物， 增加剂量。 性格变化导致“触发点”以上 其致死率随剂量的增加而急剧增加 其意义 我们的工作是希望深入了解其作用机制 N-乙酰-L-半胱氨酸作为AN解毒剂，并能够理解， 从分子水平探讨急性AN中毒的发病机制。 了解中毒的分子基础应该可以让我们 针对这些机制设计更具体的解毒剂。

Acrylonitrile (AN) is a chemical widely used in the production of synthetic fibers, plastics and rubber. AN is a reactive chemical with an acute lethal action in experimental animals. Death in humans accidentally exposed to AN have been reported. Current industrial hygiene practices can limit the exposure of workers to AN during normal occupational procedures. However, accidental exposures to high levels can acutely affect the health of individuals involved in the production, transportation, and end use of AN. In the event of a large accidental release of AN, even the health of the general populace could be affected. AN can be oxidatively metabolized cyanide which is some ten times more toxic than the parent molecule on a molar basis. However, because of it high chemical reactivity with thiol groups in the body,the parent AN molecule is also thought to be toxic. Thus AN is a double edged sword and antidotal measures must take into account both the cyanide component and the "other" component(s) of its toxic action. Unfortunately, the currently recommended antidotal therapy for AN poisoning focuses solely on the management of cyanide intoxication. Our objective is to mimic an acute dermal AN exposure and to measure the ability of thiol containing antidotes, e.g. N-acetyl-L- cysteine, to increase the clearance of acrylonitrile from the circulation. This will minimize the time available for AN to chemically react with protein thiol groups in vivo. Further we propose to ascertain whether the ability of N-acetyl-L-cysteine to decrease covalent binding, possibly by increasing AN clearance, is a direct effect of N-acetyl-L-cysteine or if it is acting indirectly through serving as a precursor for glutathione. In addition, we plan to use one and two dimensional gel electrophoresis to separate the specific tissue proteins to which AN is covalently bound and to use N-terminal sequencing of the blotted gels to identify these proteins. The ability of thiol containing antidotes to protect these proteins from AN covalent binding will be measured. Finally, we plan to use AN metabolite excretion patterns and the labeling by AN of specific amino acid sites in hemoglobin, as biomarkers for changes in AN disposition with increasing dose. Dispositional changes lead to a "Trigger Point" above which lethality increases sharply with dose. The significance of this work is that we hope to gain some insight into the mechanism of action of N-acetyl-L-cysteine as AN antidote and to be able to understand, at the molecular level, the mechanisms involved in acute AN intoxication. Understanding the molecular basis for intoxication should allow us to design antidotes directed more specifically toward these mechanisms.