ACUTE ACRYLONITRILE INTOXICATION--ANTIDOTAL ASSESSMENT

急性丙烯腈中毒——解毒评估

• 批准号: 2518637
• 负责人: FREDERICK W BENZ
• 金额: $ 15.07万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518637
• 关键词: acetylcysteine; antidotes; biomarker; blood chemistry; chemical binding; covalent bond; cyanides; dosage; drug screening /evaluation; environmental toxicology; gel electrophoresis; glutathione; hemoglobin; laboratory rat; pharmacokinetics; plastics; poisoning; protein sequence; skin absorption

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.

丙烯腈(AN)是一种广泛用于生产 合成纤维、塑料和橡胶。AN是一种活性化学物质，与 实验动物的一种急性致死行为。人类的死亡 意外接触到AN已有报道。当前的工业 卫生习惯可以限制工人在正常情况下接触空气。 职业程序。然而，意外暴露在高水平下 会严重影响参与生产的个人的健康， 运输，以及AN的最终使用。在发生重大意外事件时 释放一个，甚至是普通民众的健康可能是 受影响。AN可以是氧化代谢的氰化物，大约有十个 按摩尔计算，其毒性是母体分子的两倍。然而， 由于它与体内的硫醇基团具有很高的化学反应活性， 母体分子也被认为是有毒的。 因此，这是一把双刃剑，必须采取反措施 既要考虑氰化物成分，又要考虑其“其他”成分(S 有毒行为。不幸的是，目前推荐的解毒剂 中毒的治疗完全集中在氰化物的管理上 喝醉了。我们的目标是模拟急性皮肤AN暴露和 测定含硫醇解毒剂的能力，如N-乙酰-L- 半胱氨酸，以增加丙烯腈从 发行量。这将最大限度地减少可用于 在体内与蛋白质硫醇基团发生化学反应。此外，我们建议 确定N-乙酰-L-半胱氨酸是否能降低 共价结合，可能通过增加间隙，是一种直接的 N-乙酰-L-半胱氨酸的作用或间接作用 作为谷胱甘肽的前体。此外，我们计划使用一个 和双向凝胶电泳法分离特定组织 AN共价结合的蛋白质和使用N-末端 对印迹凝胶进行测序以鉴定这些蛋白质。一种能力 含有硫醇的解毒剂来保护这些蛋白质免受共价 将测量绑定。最后，我们计划使用一种代谢物 排泄模式与特定氨基酸位点的标记 在血红蛋白中，作为变化的生物标志物 剂量越来越大。性情变化导致以上的“触发点” 其致命性随着剂量的增加而急剧增加。这件事的意义 我们的工作是希望对其作用机制有一些了解 将N-乙酰-L-半胱氨酸作为解毒剂，并能够理解，在 在分子水平上，涉及急性中毒的机制。 了解醉酒的分子基础应该能让我们 针对这些机制设计更具体的解毒剂。