Naphthalene and
2-methylnaphthalene cause a highly organo- and species-selective lesion of the pulmonary bronchiolar epithelium in mice.
Naphthalene- but not 2-methylnaphthalene-induced pulmonary bronchiolar injury is blocked by prior administration of the
cytochrome P-450 monooxygenase inhibitor
piperonyl butoxide, thus suggesting that metabolism by
enzymes other than the P-450
monooxygenase inhibitor
piperonyl butoxide, thus suggesting that metabolism by
enzymes other than the P-450
monooxygenases may be important in 2-methylnaphthalene-induced
lung injury. Since many of the
polycyclic aromatic hydrocarbons are metabolized by the
prostaglandin endoperoxide synthetase system and because detectable
xenobiotic metabolizing activity has been associated with the
prostaglandin synthetases in the Clara cell, the studies reported here were done to compare
NADPH-versus arachidonate-dependent metabolism of
naphthalene and
2-methylnaphthalene in vitro and to determine whether
indomethacin, a potent inhibitor of
prostaglandin biosynthesis, was capable of blocking the in vivo toxicity of these two
aromatic hydrocarbons. The
NADPH-dependent metabolism of
naphthalene and
2-methylnaphthalene to covalently bound metabolites in lung or liver microsomal incubations occurred at easily measurable rates. Renal microsomal
NADPH-dependent metabolism of either substrate was not detected. The formation of covalently bound
naphthalene or
2-methylnaphthalene metabolites was dependent upon
NADPH and was inhibited by the addition of
reduced glutathione,
piperonyl butoxide, and SKF 525A. Covalent binding of radioactivity from [14C]2-methylnaphthalene also was strongly inhibited by incubation in a
nitrogen atmosphere or at 2 degree. The
arachidonic acid-dependent formation of reactive metabolites from
naphthalene or
2-methylnaphthalene was undetectable in microsomal incubations from lung, liver or kidney.
Indomethacin, 1 hr before and 6 hr after the administration of 300 mg/kg
naphthalene or
2-methylnaphthalene, failed to block the pulmonary bronchiolar injury induced by these
aromatic hydrocarbons. These studies suggest that the major
enzymes involved in the metabolic activation of
naphthalene or
2-methylnaphthalene in vitro are the
cytochrome P-450 monooxygenases and that cooxidative metabolism by the
prostaglandin synthetases appears to play little role in the formation of reactive metabolites in vitro.