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. 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.