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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：
7235959
负责人：
CHARLES Vincent SMITH
金额：
$ 37.68万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
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 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7235959
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）：化学活性中间体引起许多药物和环境化学品的毒性，并通过生物分子的共价修饰导致许多人类疾病的发病机制。特定的活性氧和氮物质、自由基、自由基和其他氧化剂物质表现出不同的性质和反应性，为了预防或治疗氧化剂挑战的不利影响，我们需要了解活性中间体的性质及其作用机制。本申请中描述的研究的主要目标是阐明这些机制。以前的研究涉及氧化损伤机制中蛋白巯基的损失，但我们始终没有观察到毒理学相关模型中蛋白巯基状态的显著变化，特别是在体内。在氧化剂细胞杀伤的几种模型中，数据表明，氧化还原活性铁螯合物催化的氧化特征与组织损伤的相关性比硫醇/二硫化物氧化还原位移更密切。最近的初步数据表明，活性氮物种可能有助于显着的机制，我们研究的主要模型中的损伤，这些机制的相对贡献需要进行调查。具体目的1是检验以下假设：除二硫化物外，肝蛋白氧化的特定产物将提供体内氧化剂介导的肝坏死的分子（分子的化学定义）机制的生物标志物。尽管在氧化剂组织损伤的相关模型中没有蛋白硫醇的整体消耗，但几条证据表明，对蛋白硫醇的影响是致死性细胞损伤的重要决定因素，具体目标2中描述的研究旨在检验以下假设：区室化和分子选择性硫醇/二硫键移位及相关变化显著促进氧化剂损伤。我们采用的主要模型是基于敌草快、对乙酰氨基酚和呋塞米在体内和体外的毒性，以及用于体外研究的一组有限的模型氧化剂。对乙酰氨基酚和呋塞米的治疗用途广泛，敌草快和百草枯是广泛使用的除草剂。虽然大多数公认的人类毒性来自急性接触或过量，通常是故意的，但新出现的证据表明，长期、低剂量接触这些制剂可能造成比目前所认识到的更多的不良影响。然而，我们在这些毒物的影响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，主要集中在氧化剂诱导的肝坏死。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diquat- and acetaminophen-induced alterations of biliary efflux of iron in rats.

敌草快和对乙酰氨基酚诱导大鼠胆汁铁流出的改变。

DOI：
10.1016/0006-2952(94)90084-1
发表时间：
1994
期刊：
Biochemical pharmacology
影响因子：
5.8
作者：
Benzick,AE;Reddy,SL;Gupta,S;Rogers,LK;Smith,CV
通讯作者：
Smith,CV

An image database of Drosophila melanogaster wings for phenomic and biometric analysis.

用于表组和生物特征分析的果蝇翅膀图像数据库。

DOI：
10.1186/s13742-015-0065-6
发表时间：
2015
期刊：
GigaScience
影响因子：
9.2
作者：
Sonnenschein,Anne;VanderZee,David;Pitchers,WilliamR;Chari,Sudarshan;Dworkin,Ian
通讯作者：
Dworkin,Ian

Gene structure for mouse glutathione reductase, including a putative mitochondrial targeting signal.

小鼠谷胱甘肽还原酶的基因结构，包括假定的线粒体靶向信号。

DOI：
10.1006/bbrc.1997.7153
发表时间：
1997
期刊：
Biochemical and biophysical research communications.
影响因子：
0
作者：
Tamura,T;McMicken,HW;Smith,CV;Hansen,TN
通讯作者：
Hansen,TN

Identification of modified tryptophan residues in apolipoprotein B-100 derived from copper ion-oxidized low-density lipoprotein.

源自铜离子氧化低密度脂蛋白的载脂蛋白 B-100 中修饰色氨酸残基的鉴定。

DOI：
10.1021/bi991464g
发表时间：
1999
期刊：
Biochemistry
影响因子：
2.9
作者：
Yang,C;Gu,ZW;Yang,M;Lin,SN;Siuzdak,G;Smith,CV
通讯作者：
Smith,CV

Analyses of glutathione reductase hypomorphic mice indicate a genetic knockout.

对谷胱甘肽还原酶低效小鼠的分析表明基因敲除。

DOI：
10.1093/toxsci/kfh268
发表时间：
2004
期刊：
Toxicological sciences : an official journal of the Society of Toxicology.
影响因子：
0
作者：
Rogers,LynetteK;Tamura,Toshiya;Rogers,BryanJ;Welty,StephenE;Hansen,ThomasN;Smith,CharlesV
通讯作者：
Smith,CharlesV