LINOLEIC ACID DIOLS--A NEW CLASS OF CYTOTOXIC COMPOUNDS

描述：（改编自申请人的摘要） 本研究项目的目的是确定毒理学和 一类独特的细胞毒性化合物的临床意义，即， 亚油酸单环氧化物的二醇代谢物（白细胞毒素和 异白细胞毒素）。 这些单环氧化物在高水平的血清中被发现， 严重烧伤合并急性呼吸窘迫综合征（ARDS）患者 并被证明会导致冠状动脉心脏骤停和严重的肺水肿， 实验动物 然而，研究人员最近的结果显示， 白细胞毒素和异白细胞毒素仅在含有 环氧水解酶 这表明先前的病理影响 归因于环氧化物，实际上归因于二醇代谢物。 基于 基于这些结果，本申请的具体目的是：（1） 化学合成的单环氧化合物和相应的二醇异构体 （2）对合成的化合物进行生物活性分析 使用体外（心肌细胞）和转基因小鼠模型的化合物，（3） 使用异源表达系统来鉴定人酶途径， 导致这些化合物的产生，和（4）识别和量化 急性呼吸窘迫患者血清中的这些化合物 综合征 这些具体目标旨在检验以下假设： 亚油酸二醇直接引起或介导先前 归因于母体环氧化物和酶催化的二醇 形成是速率限制步骤。 这项工作将为 开发特定的环氧化物水解酶抑制剂，以防止 这些化合物在人类急性炎症期间形成。

DESCRIPTION: (Adapted from the Applicant's Abstract) The long-term objective of this research project is to determine the toxicological and clinical significance of a unique class of cytotoxic compounds, namely, the diol metabolites of monoepoxides of linoleic acid (leukotoxin and isoleukotoxin). These monoepoxides are found at high levels in the serum of patients with severe burns and acute respiratory distress syndrome (ARDS) and was shown to cause coronary cardiac arrest and severe lung edema in experimental animals. Recent results by the investigator, however, show that leukotoxin and isoleukotoxin are toxic only in cells which contain epoxide hydrolase. This suggests that the pathological effects previously attributed to the epoxides are actually due to the diol metabolites. Based on these results, the specific aims of this application are to: (1) Chemically synthesize the monoepoxides and corresponding diol isomers of linoleic acid, (2) Analyze the biological activity of these synthesized compounds using in vitro (cardiac myocytes) and transgenic mouse models, (3) Use a heterologous expression system to identify human enzyme pathways which lead to the production of these compounds, and (4) Identify and quantify these compounds in the serum of patients with acute respiratory distress syndrome. These specific aims are designed to test the hypothesis that linoleic acid diols directly cause or mediate effects that were previously attributed to the parent epoxides and that enzymatically catalyzed diol formation is the rate limiting step. This work will provide a basis for developing specific inhibitors of epoxide hydrolases in order to prevent the formation of these compounds during acute inflammation in humans.