METABOLIC ACTIVATION OF AIR TOXICS IN ASTHMATIC MONKEYS

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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.