METABOLIC ACTIVATION OF AIR TOXICS IN ASTHMATIC MONKEYS

哮喘猴体内空气毒物的代谢激活

• 批准号: 8357260
• 负责人: Alan R Buckpitt
• 金额: $ 2.52万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357260
• 关键词: 1-naphthol; Accounting; Acute; Air; California; Comparative Study; Dose; Epidemiology; Epoxy Compounds; Exposure to; Funding; Glycols; Grant; Health; Hydrocarbons; Hyperplasia; Injury; Kinetics; Macaca mulatta; Metabolic Activation; Metabolism; Microsomes; Monkeys; Mus; Naphthalene; Naphthoquinones; Nasal Epithelium; National Center for Research Resources; Neoplasms; Nose; Olfactory Epithelium; Predisposition; Preparation; Primates; Principal Investigator; Process; Protein Binding; Rat-1; Rattus; Research; Research Infrastructure; Resources; Rodent; Sampling; Site; Source; Time; Tissues; Toxic effect; United States National Institutes of Health; adduct; cell type; cost; cytotoxicity; exposed human population; nonhuman primate

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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 萘是一种挥发性碳氢化合物，在啮齿类动物急性暴露后会引起剂量、种类和细胞类型依赖性的细胞毒性，在终生暴露后会引起增殖/肿瘤。毒性依赖于代谢激活，而反应性代谢物蛋白结合与组织和部位敏感性相关。人类接触萘是一种普遍现象，而且是通过各种与燃烧有关的来源发生的，但缺乏人类接触对健康影响的流行病学证据。在大鼠和猕猴的鼻黏膜上皮细胞中，研究了被认为对萘的毒性至关重要的过程的比较研究。 目前正在进行的研究集中于确定从易感组织(大鼠和小鼠鼻嗅觉上皮，小鼠呼吸道)和非靶组织(大鼠呼吸道)制备的微体与非人类灵长类组织相比，在微体中萘代谢的初始步骤的动力学。底物周转率最高的是大鼠鼻嗅觉上皮(30nmoles/mg/min)。小鼠嗅觉微粒体的代谢率(16.4)是大鼠的一半。猕猴鼻甲的微粒体数不到小鼠的10%。经解剖的小鼠呼吸道微粒体能以10.9nmole/mg/min的速度催化NA代谢，而大鼠呼吸道的代谢速度仅为此速度的5%。大部分代谢产物为1，2-环氧化物的GSH结合物。在较长的孵育时间内，除大鼠呼吸道外，所有制剂中均可观察到二环氧化物与GSH加合物的diGSH偶联物。在使用的条件下，不到12%的 产生的代谢物以1-萘酚或二氢二酚为主。小鼠呼吸道、小鼠和大鼠鼻上皮的微粒体在NA环氧化反应中表现出高度的立体选择性(20：1)，而大鼠呼吸道和猴鼻标本则不具有立体选择性。组织对NA诱导的损伤的敏感性与高底物周转率相关；猴子鼻上皮的新陈代谢比大鼠嗅觉上皮低10-50倍。