METABOLIC ACTIVATION OF AIR TOXICS IN ASTHMATIC MONKEYS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 萘是一种挥发性碳氢化合物，在啮齿类动物中，急性暴露后会导致剂量、物种和细胞类型依赖性细胞毒性，终生暴露后会导致增生/瘤形成。 毒性取决于代谢活化，反应性代谢产物蛋白结合与组织和部位易感性相关。 人类暴露于萘是普遍的，并发生从各种燃烧有关的来源，但人类暴露的健康影响的流行病学证据缺乏。 在大鼠和恒河猴的鼻上皮中进行了比较研究，检查了被认为对萘毒性至关重要的过程。 目前正在进行的研究重点是确定与非人灵长类动物相比，从易感组织（大鼠和小鼠鼻嗅上皮、小鼠气道）和非靶组织（大鼠气道）制备的微粒体中萘代谢初始步骤的动力学。 底物周转率最高的是大鼠鼻嗅上皮（30 nmole/mg/min）。 小鼠嗅微粒体的代谢率（16.4）是大鼠的一半。 猴鼻甲骨的微粒体小于小鼠微粒体的10%。 来自解剖的小鼠气道的微粒体以10.9 nmole/mg/min催化NA代谢，而大鼠气道中的代谢以该速率的5%发生。 大多数代谢产物被认为是1，2-环氧化物的GSH结合物。 在较长的孵育时间，在除大鼠气道外的所有制剂中观察到二环氧化物的diGSH缀合物和二醇环氧化物和1，4-萘醌的GSH加合物。在所使用的条件下， 产生的总代谢物由1-萘酚或二氢二醇构成。来自小鼠气道、小鼠和大鼠鼻嗅上皮的微粒体在NA环氧化中表现出高度的立体选择性（20：1），而大鼠气道和猴鼻样品没有。 组织对NA诱导的损伤的敏感性与底物周转率高相关;猴鼻上皮的代谢比大鼠嗅上皮低10-50倍。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Naphthalene is a volatile hydrocarbon which causes dose, species and cell type dependent cytotoxicity after acute exposure and hyperplasia/neoplasia after lifetime exposures in rodents. Toxicity depends upon metabolic activation, and reactive metabolite protein binding correlates with tissue and site susceptibility. Human exposure to naphthalene is universal and occurs from a variety of combustion-related sources but epidemiologic evidence for health effects of human exposure are lacking. Comparative studies examining processes thought to be essential to the toxicity of naphthalene have been examined in nasal epithelium of rats and Rhesus macaques. The studies currently being conducted are focused on determining the kinetics for the initial step in naphthalene metabolism in microsomes prepared from susceptible (rat and mouse nasal olfactory epithelium, mouse airways) and non target (rat airways) tissues in comparison to non-human primates. The highest rates of substrate turnover were in the rat nasal olfactory epithelium (30 nmoles/mg/min). Rates of metabolism in mouse olfactory microsomes (16.4) were half those in the rat. Microsomes from monkey nasoturbinates were less than 10% those of the mouse. Microsomes from dissected murine airways catalyzed NA metabolism at 10.9 nmole/mg/min whereas metabolism in rat airways occurred at 5% of this rate. The majority of the metabolites were accounted for as GSH conjugates of the 1,2-epoxide. At longer incubation times diGSH conjugates of the diepoxide and GSH adducts of the diol epoxide and 1,4-naphthoquinone were observed in all preparations except rat airway. Under the conditions used, less than 12% of the total metabolites produced were accounted for by 1-naphthol or dihydrodiol. Microsomes from mouse airways, mouse and rat nasal olfactory epithelium showed a high degree of stereoselectivity in NA epoxidation (20:1), rat airways and monkey nasal samples did not. Tissue susceptibility to NA-induced injury correlates with high rates of substrate turnover; metabolism in the nasal epithelium of monkeys is 10-50 fold lower than in rat olfactory epithelium.