TOXICOKINETICS AND DRUG TOXICITY

该计划项目有两个目标。第一个是 确定功能和结构机制 对反应性代谢物引起的致死细胞损伤负责。 项目I“反应性的最终共同途径”的目标 代谢物损伤：钙离子稳态异常“是为了完成 正在进行的工作记录了钙监管机构的损害 介导反应性代谢产物所致肝坏死的部位 (对乙酰氨基酚、溴苯、CC14、敌草胺)，并调查 膜钙通透性的变化对钙离子的影响 质膜和内质网中的ATPase活性 损伤。项目II“脂质的化学机制”的目标 氧化反应代谢物中的过氧化和硫醇氧化 用化学方法定义了脂膜的作用机制 敌草快和蛋白硫醇的过氧化和蛋白质硫醇氧化 对乙酰氨基酚，以确定敌草快的效果， 活性氧介导的肝铁复合体肝坏死 和体内代谢，并确定其影响 去铁胺和硫酸亚铁的这些参数。目标 项目III，“烷基化活性代谢物的研究” 新的质谱学技术“是为了表征 多肽加合物的结构及取代基的反应机理 呋喃并利用这一知识阐明 亲电体的共价结合基于分子的“硬度” 它们的亲电性以及它们作为底物的能力 谷胱甘肽-S-转移酶。项目四“氧气”的目标 氧疗和缺血时代谢物引发的损伤- 回流条件“是为了确定是否存在脂质 过氧化或蛋白质硫醇氧化产物及其 发病机制的重要性是活性氧损伤，并确定 血管活性或趋化性二十烷类产物的存在和 活性氧作为一种抗氧化剂的致病作用 刺激或调节二十烷类化合物形成的催化剂。第二 PPG的目标是将基本发现和 项目I-LV中的方法学用于临床研究和 在实验治疗学中的应用(项目V：“氧气 新生儿代谢物引发的损伤；“项目VI：”氧气 成人危重病医学中代谢物引发的损伤 项目VII：“GSH动态平衡和GSSG还原酶抑制 《BCNU治疗在人》)。基础研究中获得的知识 应该能为我们提供重要的新见解 反应性致死细胞损伤的机制 代谢物。临床研究应该证明和定义 这些机制与改进药物和药物治疗的相关性 由缺血引起的疾病。

The program project has two objectives. The first is the identification of the functional and structural mechanisms responsible for reactive metabolite-induced lethal cell injury. The goals of Project I, "Final Common Pathway for Reactive Metabolite Injury: Abnormal Ca2+ Homeostasis," are to complete the work in progress documenting that lesions at calcium regulatory sites mediate reactive metabolite-induced hepatic necrosis (acetaminophen, bromobenzene, CC14, diquat) and to investigate the role of changes in membrane calcium permeability versus calcium- ATPase activity in the plasma membrane and endoplasmic reticulum lesions. The goals of Project II, "Chemical mechanisms of Lipid peroxidation and Thiol Oxidation in Oxidative Reactive metabolite Injury," are to define chemically the mechanisms of lipid membrane peroxidation and protein thiol oxidation after diquat and acetaminophen, to determine the effects of diquat-initiated, reactive oxygen-mediated hepatic necrosis on hepatic iron complexes and metabolism in vivo and to determine the effects of desferrioxamine and ferrous sulfate of these parameters. The goals of Project III, "Studies of Alkylating Reactive Metabolites Using Novel Mass Spectrometric Techniques," are to characterize the structure of peptide adducts and reaction mechanisms of substituted furans and to utilize this knowledge to elucidate principles for the covalent binding of electrophiles based on the "hardness" of their electrophilicity and on their ability to serve as substrates for GSH-S-transferases. The goals of Project IV, "Oxygen Metabolite-Initiated Injury in Oxygen Therapy and in Ischemia- Reflow condition," are to determine the presence of lipid peroxidation or protein thiol oxidation products and their pathogenetic importance is reactive oxygen injury and to determine the presence of vasoactive or chemotactic eicosanoid products and the pathogenetic importance of reactive oxygen serving as a calalyst to stimulate or modulate eicosanoid formation. The second objective of the PPG is the transfer of basic discoveries and methodologies in Projects I-lV to clinical investigation and applications in experimental therapeutics (Project V: "Oxygen Metabolite-Initiated Injury in Neonates;" Project VI: "Oxygen Metabolite-Initiated Injury in Adult Critical Care Medicine;" Project VII: "GSH Homeostasis and GSSG Reductase Inhibition after BCNU Therapy in Man"). The knowledge obtained in the basic studies should provide important new insights into the fundamental mechanisms responsible for lethal cell injury by reactive metabolites. The clinical studies should demonstrate and define the relevance of these mechanisms for improved therapy of drug and ischemia-induced diseases.