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Metabolism and cytotoxicity of naphthalene oxide in the isolated perfused mouse lung.

S. Kanekal,C. G. Plopper,D. Morin,A. Buckpitt

Published 1990 in Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

Naphthalene produces selective injury to Clara cells in the mouse in vivo and in the isolated perfused lung. To investigate the role of circulating reactive metabolites in lung injury, the stability, metabolism and cytotoxicity of naphthalene oxide, a reactive intermediate, were examined in the perfused mouse lung. The T1/2 of naphthalene oxide is 4 min in Waymouth's medium. Addition of 5% bovine serum albumin to the medium increased the half-life of the epoxide to 11 min. Perfusion of the lung with 0.2 or 2 mumol of naphthalene oxide decreased pulmonary reduced glutathione levels to 62 and 42% of control, respectively. 1,4-Naphthoquinone and naphthol-glucuronide represented 36 and 25% of the total polar metabolites isolated after infusion of naphthalene oxide, whereas dihydrodiol and thioether conjugates were minor metabolites. In comparison, thioethers and dihydrodiol were the primary metabolites isolated from lungs perfused with [14C]naphthalene. Histologic examination of the lungs fixed 4 hr after infusion of naphthalene oxide (0.25-1.0 mumol/60 min) revealed selective vacuolation and necrosis of Clara cells, significant decreases in the mass of bronchiolar Clara cells and increases in the mass of vacuolated cells. Injury to lungs perfused with naphthalene or secondary metabolites such as naphthoquinones, 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene was less dramatic. In contrast to other studies implicating quinones as mediators of aromatic hydrocarbon toxicity, the current work suggests that epoxides play a significant role in naphthalene-induced lung injury. This investigation also demonstrates that circulating epoxides are capable of eliciting selective Clara cell injury.

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