Mechanistic studies of pulmonary toxicity of styrene

据报告，职业性苯乙烯接触的广泛影响可引起严重的急性毒性效应。 已发现吸入苯乙烯对人和动物产生呼吸道毒性。总体目标 本建议中描述的研究的一个方面是研究急性呼吸道疾病的生化机制， 苯乙烯引起的毒性。我们的初步研究表明，对位取代卤素“放大” 苯乙烯的细胞毒性。这些苯乙烯类似物是用于反应机理研究的优良模型化合物。 通过比较它们的毒性潜力和它们的生化行为来确定毒性作用。苯乙烯的毒性一直是 提示由细胞色素P450酶介导，特别是CYP 2 E1和CYP 2F 2。亲电 已经提出苯乙烯7，8-环氧化物是导致苯乙烯毒性的毒性代谢物。我们 假设苯乙烯毒性与细胞蛋白质修饰有关， 苯乙烯。作为本项目的初始步骤，我们将（1）将结构-活性关系研究扩展到 确定乙烯基（环氧化物前体）在苯乙烯毒性中的重要性;（2）开发分析 苯乙烯和卤代苯乙烯对蛋白质修饰的研究进展;（3）研究环氧化合物 水解酶转基因细胞，探讨环氧代谢产物在苯乙烯毒性中的作用;（4）鉴定反应性 卤化苯乙烯衍生物的代谢物;和（5）评估苯乙烯和卤化苯乙烯衍生物的动力学。 苯乙烯。为了探索这一假设，我们将确定（1）蛋白质修饰与 苯乙烯和卤代苯乙烯诱导的毒性强度;（2）蛋白质修饰之间的关联 和细胞谷胱甘肽含量/谷胱甘肽S-转移酶活性/环氧化物水解酶活性 苯乙烯和卤代苯乙烯。我们的期望是，蛋白质修饰与卤化成比例， 苯乙烯潜在毒性及提高苯乙烯衍生物反应活性和制备环氧化物的因素 代谢物的转化增强了蛋白质修饰和呼吸毒性。

Wide range effects of occupational styrene exposure have been reported to cause severe acute toxic effects. Inhaled styrene has been found to produce respiratory toxicity in human and animals. The overall objective of the research described in this proposal is to investigate the biochemical mechanism of acute respiratory toxicity induced by styrene. Our preliminary studies showed that para-substituted halogens "amplify" cytotoxicity of styrene. These styrene analogues are excellent model compounds for mechanistic studies of toxic action by comparing their toxicity potentials with their biochemical behaviors. Styrene toxicity has been suggested to be mediated by cytochrome P450 enzymes, specifically CYP2E1 and CYP2F2. Electrophilic styrene 7,8-epoxide has been proposed to be toxic metabolite responsible for styrene toxicity. We hypothesize that styrene toxicity is associated with cellular protein modification by epoxide metabolite of styrene. As initial steps for this project, we will (1) extend the structure-activity relationship study to determine the importance of the vinyl group (epoxide precursor) in styrene toxicity; (2) develop analytical approaches to determine protein modification by styrene and halogenated styrenes; (3) develop epoxide hydrolase transgenic cells to explore the role of epoxide metabolite in styrene toxicity; (4) identify reactive metabolites of halogenated styrene derivatives; and (5) to assess kinetics of styrene and halogenated styrenes. To probe the hypothesis, we will determine (1) association between protein modification and toxicity intensity induced by styrene and halogenated styrenes; (2) association beween protein modification and cellular glutathione content/glutathione S-transferase activity/epoxide hydrolase activity after exposure to styrene and halogenated styrenes. Our expectation is that protein modification is propotional to halogenated styrene toxicity potentials and that factors to increase reactivity of styrene derivatives and to make epoxide metabolites accumalted enhance protein modification and respiratory toxicity.