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.