Extrapolation of toxicologic data derived in animals to the human is a complex task that is especially difficult with those agents where there are marked species differences in the response and where there is a lack of epidemiologic data. There are a number of volatile industrial and environmental chemicals including naphthalene, dichloroethylene and trichloroethylene that result in dose-dependent necrosis of the pulmonary Clara cells of the mouse but in no injury to rat or hamster lung. Naphthalene-induced lung injury depends upon cytochrome P450 mediated metabolism and correlates with the glutathione (GSH) depletion and covalent binding by reactive metabolites to pulmonary macromolecules. However, covalent binding in nontarget tissues was higher than in the lung suggesting that then nature of reactive, potentially cytotoxic metabolites differed. Subsequent examination of the microsomal metabolism of naphthalene has demonstrated an excellent correlation between the formation of a particular reactive metabolite (trapped as a GSH adduct) and the species/organo-selectivity in naphthalene-induced cytotoxicity. These studies propose to determine whether urinary mercapturic acids derived from these GSH adducts can be used as a probe to examine the activity and metabolic selectivity of the pulmonary monooxygenase system. The importance stems from the fact that in vitro studies of human lung P450 xenobiotic metabolism have consistently failed to demonstrate significant activity possible because of artifacts introduced during tissue preparation. The goal of these studies is to provide a means to examine interindividual variations in activity and selectivity of the human lung monooxygenases. The proposed studies will develop methods for the extraction and HPLC separation and quantitation of urinary naphthalene mercapturates. Each of the isomeric GSH adducts will be administered to animals to determine their metabolic fate. The excretion of each of the isomers will be monitored in both rats and mice exposed to naphthalene by inhalation and by ip injection to determine whether the rates of excretion of the isomers are dependent upon the first pass organ (liver or lung) and the species exposed.
