Reactive Metabolites in Drug Toxicity

药物毒性中的反应性代谢物

基本信息

批准号：
7653980
负责人：
ROBERT P HANZLIK
金额：
$ 27.1万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-08-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7653980
关键词：
4-bromophenol Acetaminophen Area Binding Bioinformatics Bromobenzenes Cells Chemicals Clinical Complement Development Diclofenac Drug Delivery Systems Drug toxicity Event Failure Gel Halothane Hepatocyte Hepatotoxicity Injury Investments Laboratories Lead Life Liver MAP Kinase Signaling Pathways Mass Spectrum Analysis Metabolic Biotransformation Metabolism Methods Mitochondria Modification Natural Killer Cells Orthologous Gene Outcome Pathway interactions Patients Pharmaceutical Preparations Play Poison Process Protein Binding Domain Protein Databases Proteins Proteomics Reporting Resources Role Signal Pathway Signal Transduction Site Solvents Testing Thioacetamide Toxic effect Work adduct allyl alcohol analog base cost cytotoxic cytotoxicity drug candidate experience hepatotoxin member protein metabolite protein protein interaction public health relevance response thiobenzamide

项目摘要

DESCRIPTION (provided by applicant): Many simple organic molecules including solvents, agrichemicals, drugs and drug candidates become cytotoxic upon biotransformation to reactive electrophilic metabolites. The liver is a major site of foreign compound metabolism and is often a major target for drug and chemical toxicity. Hepatotoxicity remains the single most important factor in the failure of drug candidates late in development (when such failure is extremely expensive in terms of lost investment of resources), and of approved drugs early in open clinical usage (when the cost of failure can also include severe or even fatal injury to patients). Understanding the mechanism(s) by which chemicals cause cytotoxic liver injury remains a major challenge of enormous scientific and practical importance. A major focus of our laboratory has been the identification and characterization of chemically reactive metabolites, the protein adducts they form in living cells, and the specific proteins that become adducted. We have hypothesized that there exists a common subset of cellular proteins whose covalent modification by reactive metabolites initiates cytotoxic events through intracellular signaling mechanisms. Our recent work has identified 28 such candidate proteins. Bioinformatic analysis reveals that 21 of them interact with 165 partner proteins, many of which are members of the MAP kinase signaling pathway. Encouraged by these observations, we propose to test our original hypothesis more thoroughly by (1) expanding significantly the list of known target proteins for chemically-reactive metabolites of several paradigm hepatotoxicants to look for commonality (i.e. functional proteomics); (2) applying bioinformatic methods to analyze target proteins and their first-neighbor interacting partners to uncover common signaling pathways that lead to cytotoxic outcomes; (3) testing the hypothesis that hepatocytes are able to recognize and respond to adducted proteins per se by delivering pre-adducted proteins directly into hepatocytes using protein transduction domains and observing the cells for cytotoxic responses and/or changes in intracellular signaling pathways associated with hepatotoxicity. PUBLIC HEALTH RELEVANCE: Many drugs and chemicals give rise to chemically-reactive metabolites that modify cellular proteins leading to cytotoxicity. We have identified certain proteins whose modification may play a general role in this process, and we now propose to search more broadly for other such proteins and their interacting cellular partners that may form part of a general process underlying reactive metabolite cytotoxicity.

描述（由申请人提供）：许多简单的有机分子，包括溶剂，农业化学物质，药物和候选药物，在生物转化对反应性亲电代谢物的生物转化后变为细胞毒性。肝脏是外国复合代谢的主要部位，通常是药物和化学毒性的主要靶标。肝毒性仍然是候选药物失败的最重要因素（当这种失败在资源投资损失方面非常昂贵时），并且在开放临床用途的早期批准的药物（当失败的成本也可能包括对患者的严重甚至致命伤害时）。了解化学物质引起细胞毒性肝损伤的机制仍然是巨大的科学和实际重要性的主要挑战。我们实验室的主要重点是鉴定和表征化学反应性代谢产物，它们在活细胞中形成的蛋白质加合物以及加成的特定蛋白质。我们假设存在一个常见的细胞蛋白子集，其通过反应性代谢物通过细胞内信号传导机制启动细胞毒性事件，其共价修饰。我们最近的工作已经确定了28种此类候选蛋白。生物信息学分析表明，其中21个与165种伴侣蛋白相互作用，其中许多是MAP激酶信号通路的成员。在这些观察结果的鼓励下，我们建议通过（1）显着扩展已知靶蛋白的列表，以更彻底地检验我们的原靶蛋白列表，用于几种范式肝毒性剂的化学反应性代谢产物，以寻求共同点（即功能蛋白质组学）；（2）应用生物信息学方法来分析靶蛋白及其第一邻外伴侣，以发现导致细胞毒性结果的常见信号传导途径；（3）测试以下假设：肝细胞能够使用蛋白质转录结构域直接将预添加的蛋白质直接输送到肝细胞中，以识别并响应加成的蛋白质本质，并观察细胞的细胞毒性反应和/或与肝毒性相关的细胞内信号传导途径中的细胞毒性反应和/或变化。公共卫生相关性：许多药物和化学物质会导致化学反应性代谢产物，从而改变细胞蛋白，从而导致细胞毒性。我们已经确定了某些蛋白质的修饰可能在此过程中起一般作用，现在我们建议更广泛地搜索其他此类蛋白质及其相互作用的细胞伴侣，这些蛋白可能构成反应性代谢物细胞毒性的一般过程的一部分。