GLUTATHIONE LEVELS IN AIRWAYS OF INFANT MONKEYS EXP TO O3 WITH & WITHOUT HDMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：萘（NA）和1-硝基萘（1-NN）是一种被肺细胞色素P450单加氧酶生物活化并消耗谷胱甘肽的环境空气污染物。反应性代谢物与细胞蛋白共价结合，这一过程与啮齿动物模型中与这些药物相关的细胞损伤有关。啮齿类动物模型在评估需要生物激活的化学物质的重要性方面的相关性尚不清楚，因为灵长类动物的细胞色素P450单加氧酶活性比啮齿动物低10到100倍。除了是生物活性毒物的靶点外，气道也是急性炎症反应的最易感部位之一。炎症至少在肝外组织中导致细胞色素P450依赖性代谢的强烈抑制。最近的工作已经建立并验证了一种涉及暴露于屋尘螨抗原（HDMA）和臭氧（O3）的人类哮喘灵长类动物模型。因此，这些研究旨在测量恒河猴体内反应性代谢产物蛋白质加合物的形成和特性，并确定产生哮喘反应的治疗是否会改变蛋白质加合物的生成速率和性质。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: Naphthalene (NA) and 1-nitronaphthalene (1-NN) are ambient air pollutants which undergo bioactivation by pulmonary cytochrome P450 monooxygenases and deplete Glutathione. Reactive metabolites become bound covalently to cellular proteins and this process has been implicated in cellular injury associated with these agents in rodent models. The relevance of rodent models in assessing the importance of chemicals which require bioactivation is not clear because of the 10 to 100 fold lower activities of cytochrome P450 monooxygenases in primates compared to rodent lungs. Besides being a target for bioactivated toxicants, the airway is also one of the most susceptible sites for acute inflammatory response. Inflammation results in a strong suppression of cytochrome P450 dependent metabolism at least in extrahepatic tissues. Recent work has established and validated a primate model for human asthma which involves exposure to house dust mite antigen (HDMA) and ozone(O3). Accordingly these studies were designed to measure the formation of, and identity of reactive metabolite protein adducts in rhesus macaques and to determine whether treatments which produce an asthmatic response alter the rates and or nature of protein adducts generated.