MECHANISM OF ACETAMINOPHEN HEPATOTOXICITY

对乙酰氨基酚(APAP)是一种广泛使用的、安全的解热止痛药， 当过量服用时，会导致严重的肝脏坏死。肝毒性 已被证明是APAP对微粒体激活的结果 首先耗尽谷胱甘肽(GSH)储备然后结合的电泳体 共价连接到关键的电池组件。拟议的研究旨在 阐明APAP导致细胞死亡的机制(S)。以下是 具体问题将被解决：1)共价结合如何 不同的亚细胞细胞器与细胞的发育有关 肝毒性？2)APAP如何改变细胞器结构和 与肝毒性有关的功能？3)毒性过程是否会导致 在发生共价结合后，APAP毒性会被调节吗？4)会吗 GSH对APAP肝毒性有额外的保护作用 最大共价结合发生了吗？5)脂质的作用是什么 亚细胞器过氧化反应在APAP发病中的作用 肝脏毒性？该方法将涉及确定以下各项的顺序 肝细胞发生的生化和形态改变 在暴露于肝毒性浓度的APAP之后。 具体来说，我们将研究APAP的剂量和时间响应曲线 电泳性共价结合到特定细胞器，并与 APAP对细胞器结构和功能的影响及其相互关系 对APAP急性肝毒性的影响。特别关注 将用于阐明APAP对质膜的影响 结构和功能。此外，还将测量脂质过氧化反应。 在特定细胞器中，谷胱甘肽会耗尽或增强 被用来在监测选定的 来自剂量和时间研究的参数。拟议的研究将 阐明在APAP中毒期间发生的事件，并将允许 开发预防重症肺炎的合理替代疗法 暴露于正常肝毒性剂量的APAP和其他 肝毒素。

Acetaminophen (APAP) is a widely used, safe, antipyretic analgesic which, when taken in excess doses, causes seveere hepatic necrosis. Hepatoxicity has been shown to be the result of microsomal activation of APAP to an electrophile which first depletes glutathione (GSH) reserves and then binds covalently to critical cell components. The proposed research is aimed at elucidating the mechnism(s) hwereby APAP causes cell death. The following specific questions will be addressed: 1) How is covalent binding to different subcellular organelles related to the development of the hepatotoxicity? 2) How is APAP alteration of organelle structure and function related to the hepatotoxocity? 3) Can the toxic process leading to APAP toxicity be modulated after covalent binding has occurred? 4) Does GSH have an additional protective role against APAP hepatotoxicity after miximal covalent binding has occurred? 5) What is the role of lipid peroxidation in subcellular organelles in the development of APAP-induced hepatotoxicity? The approach will involve determining the sequence of biochemical and morphological alterations which occur in hepatocytes subsequent to exposure to a hepatotoxic concentration of APAP. Specifically, we will study the dose and time response profile of APAP electrophile covalent binding to specific organelles and compare this with APAP effects upon organelle structure and function as well as correlate such effects to the acute hepatotoxic effects of APAP. Special attention will be given to elucidation of the effects of APAP on plasma membrane structure and function. In addition, lipid peroxidation will be measured in specific organelles and, glutathione depletion or enhancement will be employed in attempts to modulate toxicity while monitoring selected parameters from the dose and time studies. The proposed research will elucidate the events which occur during APAP poisoning and will permit the development of rational alternative therapies for the prevention of severe hepatotoxicity after exposure to normally hepatoxic doses of APAP and other hepatotoxins.