权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms Of Drug-induced Toxicities

药物引起的毒性机制

基本信息

批准号：
7968977
负责人：
Lance R Pohl
金额：
$ 140.25万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7968977
关键词：
Acetaminophen Acute Liver Failure Animal Experimentation Animal Model Annual Reports Antidiabetic Drugs Antihypertensive Agents Antioxidants Area Behavioral Biological C57BL/6 Mouse CYP2E1 gene Cholestasis Chronic Hepatitis Cirrhosis Corticosterone Diabetes Mellitus Dose Face Farming environment Genetic Polymorphism Genetically Engineered Mouse Glutathione Granuloma Halothane Hepatic Hepatoprotective Agent Herbal Medicine Immunoblot Analysis Inbred Strains Mice Industry Inhalation Anesthetics Injury Injury to Liver Interleukin-4 Knowledge Laboratories Lesion Life Ligase Link Lipids Liver Liver diseases Malignant Neoplasms Marketing Mitochondria Modeling Monitor Mus Nature Non-Steroidal Anti-Inflammatory Agents Oxidative Stress Pharmaceutical Preparations Predisposition Protein Synthesis Inhibition Proteins Proteome Psychotropic Drugs Public Health Research Research Personnel Resistance Risk Rivers Role Serum Stress Testing Time Toxic effect Toxicology Vendor adduct antimicrobial drug base cell injury chemokine cytokine drug induced liver disease drug inhalation drug mechanism novel overexpression post-market prospective

项目摘要

ANNUAL REPORT FOR 2009 1. This year we confirmed that IL-4 protects mice from AILI by increasing the synthesis of gamma-glutamylcysteinyl ligase (GCL), the rate determining step in the synthesis of the cytoprotective molecule glutathione. This was done by administering IL-4 to mice made deficient in this cytokine and showing that IL-4 treatment protected IL-4 deficient mice from severe AILI by increasing hepatic levels of GCL and glutathione. 2. This year we provide evidence suggesting that halothane-induced liver injury is caused at least in part by enhancing ER stress, which results in protein synthesis inhibition and rapid turnover of several antioxidant proteins that protect cells from injury. 3. C57BL/6 inbred mouse strain is one of the most widely used animals for research models. However, their popularity has led to the creation of several C57BL/6 mice substrains maintained within and among different vendors. In this regard, major discrepancies between C57BL/6 mice substrains have been shown in several areas of research including behavioral studies, diabetes, cancer and oxidative stress, among others. This year we have provided evidence describing similar problems in the field of toxicology. When a hepatotoxic dose of acetaminophen (APAP) was administered to substrains of C57BL/6 mice from 4 different vendors (Taconic Farms, Charles River, Harlan and The Jackson Laboratories), significant differences were found in their susceptibility to liver injury and survival. Comparing APAP bioactivation of C57BL/6J (The Jackson Laboratory; the least susceptible substrain) with C57BL/6Tac (Taconic Farms; one of the most susceptible substrains), we found by immunoblot analysis a reduced level of mitochondrial APAP protein-adducts in C57BL/6J mice compared to C57BL/6Tac that was correlated with mitochondrial levels of CYP2E1. Moreover, APAP treatment caused less mitochondrial glutathione (GSH) depletion in C57BL/6J mice compared to C57BL/6Tac. Interestingly, the levels of APAP protein-adducts and GSH in whole liver homogenates did not differ segnificantly between the two substrains. Overall, these findings suggest, for the first time, that susceptibility differences exist between different C57BL/6 mice substrains in APAP-induced liver injury model and possibly other forms of injury. It also stresses that researchers should carefully consider the appropriate C57BL/6 mice control when using genetically engineered mice on a C57BL/6 background, not only for toxicological research, but also for other biomedical studies.

2009年年度报告 1.今年，我们证实IL-4通过增加γ-谷氨酰半胱氨酰连接酶（GCL）的合成来保护小鼠免受AILI，GCL是细胞保护分子谷胱甘肽合成的速率决定步骤。这是通过将IL-4给予缺乏这种细胞因子的小鼠来完成的，并且表明IL-4治疗通过增加GCL和谷胱甘肽的肝脏水平来保护IL-4缺乏小鼠免受严重AILI。 2.今年我们提供的证据表明，氟烷诱导的肝损伤至少部分是由增强ER应激引起的，这导致蛋白质合成抑制和几种保护细胞免受损伤的抗氧化蛋白的快速周转。 3. C57 BL/6近交系小鼠是目前应用最广泛的研究模型动物之一。然而，它们的流行导致了在不同供应商内部和之间维持的几种C57 BL/6小鼠亚系的产生。在这方面，C57 BL/6小鼠亚系之间的主要差异已在包括行为研究、糖尿病、癌症和氧化应激等在内的几个研究领域中显示出来。今年，我们提供了描述毒理学领域类似问题的证据。当对来自4个不同供应商（Taconic Farms、Charles River、哈兰和The杰克逊实验室）的C57 BL/6小鼠亚系给予肝毒性剂量的对乙酰氨基酚（APAP）时，发现它们对肝损伤的易感性和存活率存在显著差异。比较C57 BL/6 J（杰克逊实验室;最不敏感的亚系）与C57 BL/6 Tac（Taconic Farms;最敏感的亚系之一）的APAP生物活化，我们通过免疫印迹分析发现，与C57 BL/6 Tac相比，C57 BL/6 J小鼠中线粒体APAP蛋白加合物水平降低，这与CYP 2 E1的线粒体水平相关。此外，与C57 BL/6 Tac相比，APAP治疗在C57 BL/6 J小鼠中引起较少的线粒体谷胱甘肽（GSH）消耗。有趣的是，APAP蛋白加合物和GSH在整个肝匀浆中的水平在两个亚株之间没有显著差异。总的来说，这些发现首次表明，在APAP诱导的肝损伤模型和可能的其他形式的损伤中，不同C57 BL/6小鼠亚系之间存在易感性差异。它还强调，研究人员在使用C57 BL/6背景的基因工程小鼠时，应仔细考虑适当的C57 BL/6小鼠对照，不仅用于毒理学研究，而且用于其他生物医学研究。