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: 8172530
• 负责人: Alan R Buckpitt
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172530
• 关键词: Actins; Acute; Air; Binding; Biochemical; Comparative Study; Computer Retrieval of Information on Scientific Projects Database; Dose; Epidemiology; Epithelial; Event; Exposure to; Funding; Gel; Grant; Health; Human; Hydrocarbons; Hyperplasia; Image; Institution; Macaca mulatta; Maps; Mass Spectrum Analysis; Metabolic; Metabolic Activation; Metabolism; Monkeys; Mus; Naphthalene; Naphthalenes; Nasal Epithelium; Neoplasms; Nose; Peptides; Predisposition; Process; Protein Binding; Proteins; Radioactive; Rattus; Reporting; Research; Research Personnel; Resources; Rodent; Silver Staining; Site; Source; Spottings; Structural Protein; Tissues; Toxic effect; Tubulin; Tumorigenicity; Two-Dimensional Gel Electrophoresis; United States National Institutes of Health; Water; adduct; cell type; cytotoxicity; exposed human population

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. 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. Adducted proteins recovered from incubations of nasal epithelium and 14C-naphthalene were separated by 2D gel electrophoresis and imaged to register radioactive proteins. Proteins visualized by silver staining on complimentary nonradioactive gels were identified by peptide mass mapping. The levels of reactive metabolite binding in incubations of Rhesus ethmo- and maxilloturbinate are similar to those in incubations of target tissues including rat septal/olfactory regions and murine dissected airway incubations. Forty one adducted spots were identified from 2D gel separations of rat olfactory epithelial proteins; 23 of these were nonredundant. In monkeys, 19 spots were identified by mass spectrometry yielding 3 nonredundant identifications. Structural proteins (actin/tubulin) were prominent targets in both species. These studies identified potential target proteins which may serve as markers closely associated with toxicity. The large differences previously reported between the rates of naphthalene metabolism to water soluble metabolites in dissected airways from mice and monkeys are not reflected in similar differences in covalent adduct formation in the nose. This raises concerns that downstream metabolic/biochemical events are very similar between the rat, a known target for naphthalene toxicity and tumorigenicity, and the Rhesus macaque, a species similar to the human.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。 从鼻上皮和14 C-萘的孵育中回收的加合蛋白通过2D凝胶电泳分离，并成像以登记放射性蛋白。 通过肽质量图谱鉴定在互补非放射性凝胶上通过银染色可视化的蛋白质。 恒河猴筛骨和上鼻甲孵育中的反应性代谢物结合水平与靶组织孵育（包括大鼠隔/嗅觉区和小鼠解剖气道孵育）中的反应性代谢物结合水平相似。 从大鼠嗅上皮蛋白的2D凝胶分离中确定了41个内收斑点;其中23个是非冗余的。 在猴中，通过质谱法鉴定了19个斑点，得到3个非冗余鉴定。 结构蛋白（肌动蛋白/微管蛋白）是这两个物种的突出目标。 这些研究确定了可能作为与毒性密切相关的标志物的潜在靶蛋白。 先前报道的小鼠和猴解剖气道中萘代谢为水溶性代谢物的速率之间的巨大差异并未反映在鼻子中共价加合物形成的类似差异中。 这引起了人们的担忧，即大鼠（萘毒性和致瘤性的已知靶标）和恒河猴（与人类相似的物种）之间的下游代谢/生化事件非常相似。