Oxidant Mechanisms in Drug-Induced Hepatic Necrosis

药物性肝坏死中的氧化机制

基本信息

批准号：
6858815
负责人：
CHARLES Vincent SMITH
金额：
$ 32.33万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6858815
关键词：
acetaminophen alkylation biomarker cytotoxicity free radical oxygen furosemide laboratory mouse laboratory rat liver disorder necrosis oxidative stress pyrazines

项目摘要

DESCRIPTION (provided by applicant): Chemically reactive intermediates cause the toxicities of a number of drugs and environmental chemicals and contribute to the pathogeneses of many human diseases through covalent modifications of biological molecules. Specific reactive oxygen and nitrogen species, radicals, free radicals, and other oxidant species exhibit different properties and reactivities, and efforts to prevent or treat the adverse effects of oxidant challenges require that we understand the properties of the reactive intermediates and the mechanisms by which they act. The principal goal of the research described in the present application is to elucidate these mechanisms. Previous studies implicated the loss of protein thiols in mechanisms of oxidant injury, but we have consistently not observed marked shifts in protein thiol status in toxicologically relevant models, particularly in vivo. In several models of oxidant cell killing, the data suggest that oxidations characteristic of those catalyzed by redox-active iron chelates correlate more closely with tissue damage than do thiol/disulfide redox shifts. Recent preliminary data indicate that reactive nitrogen species may contribute significantly to the mechanisms of injury in the primary models we study, and the relative contributions of these mechanisms need to be investigated. Specific Aim 1 is to test the hypothesis that specific products of oxidation of hepatic proteins other than disulfides will provide biomarkers of the molecular (chemist definition of molecular) mechanisms responsible for oxidant-mediated hepatic necrosis in vivo. Despite the absence of global depletion of protein thiols in relevant models of oxidant tissue damage, several lines of evidence indicate that effects on protein thiols are important determinants of lethal cell injury, and the studies described in Specific Aim 2 are designed to test the hypothesis that compartmentalized and molecularly selective thiol/disulfide shifts and related changes contribute significantly to oxidant injury. The major models we employ are based on toxicities of diquat, acetaminophen, and furosemide in vivo and in vitro, and a limited set of model oxidants for studies in vitro. Therapeutic uses of acetaminophen and furosemide are extensive, and diquat and paraquat are widely used herbicides. Although most recognized human toxicities arise from acute exposures or overdoses, often intentional, emerging evidence suggests that chronic, low dose exposures to these agents may cause more adverse effects than are appreciated at the present time. However, our major interest in the study of the effects of these toxicants is to understand the fundamental principles and concepts of drug-induced cell death in vivo, with a primary focus on oxidant-induced hepatic necrosis.

描述（由申请人提供）：化学反应性中间体引起许多药物和环境化学物质的毒性，并通过生物分子的共价修饰来促进许多人类疾病的病原体。特定的活性氧和氮种，自由基，自由基和其他氧化剂物种表现出不同的特性和反应性，以及预防或治疗氧化挑战的不利影响的努力要求我们了解反应性中间体的特性以及其作用的机制。本应用中描述的研究的主要目标是阐明这些机制。先前的研究暗示了蛋白质硫醇在氧化剂损伤机理中的丧失，但我们始终没有观察到毒性相关模型，尤其是体内蛋白质硫醇状态的明显变化。在几种氧化细胞杀死模型中，数据表明，与硫代（氧化还原活性铁螯合物催化的氧化）相比，与组织损伤相比，氧化的特征与硫醇/二硫键氧化还原偏移更紧密地相关。最近的初步数据表明，反应性氮物种可能对我们研究的主要模型中的损伤机制有显着贡献，需要研究这些机制的相对贡献。具体目的1是测试以下假设：除二硫化物以外的肝蛋白氧化的特定产物将提供分子（化学家的分子定义）机制的生物标志物，这些机制负责氧化剂介导的体内氧化剂介导的肝坏死。尽管在氧化组织损伤的相关模型中没有蛋白硫醇的全球消耗，但几种证据表明，对蛋白质硫醇的影响是致命细胞损伤的重要决定因素，并且在特定目标2中所描述的研究旨在测试假设的假设，这些假说是分子化和分子选择性硫醇/二硫化物/二硫化物/二硫化物的损害以及相关的氧化作用。我们采用的主要模型是基于diquat，对乙酰氨基酚和体外和体外速尿的毒性，以及用于体外研究的有限模型氧化剂。对乙酰氨基酚和速尿的治疗用途是广泛的，而diquat和paraquat被广泛使用。尽管大多数公认的人类毒性是由急性暴露或过量引起的，但通常是故意的，新出现的证据表明，对这些药物的慢性，低剂量暴露可能会造成比目前更大的不良反应。但是，我们对这些毒物作用的研究的主要兴趣是了解体内药物诱导的细胞死亡的基本原理和概念，主要关注氧化剂诱导的肝坏死。