Evidence for cytochrome P-450 mediated metabolism in the bronchiolar damage by naphthalene.
Intraperitoneal administration of the volatile hydrocarbon, naphthalene, resulted in severe bronchiolar epithelial cell necrosis in mice, while hepatic or renal necrosis was not observed. Pulmonary damage and mortality by naphthalene were increased by prior treatment with diethyl maleate and decreased by prior treatment with piperonyl butoxide (1600 mg/kg). SKF 525A pretreatment had no effect on naphthalene-induced pulmonary damage. Administration of [14C]naphthalene resulted in the covalent binding of radiolabel to tissue macromolecules. Highest levels of binding occurred in lung, liver and kidney. Levels of covalent binding reached a maximum 2--4 h after treatment and corresponded to rapid glutathione depletion in lung and liver. Covalent binding was dose-dependent and showed a threshold between 200 and 400 mg/kg which coincided with almost total depletion of tissue glutathione levels. Covalent binding of reactive metabolites was increased 3--4-fold by prior treatment with diethyl maleate, and was decreased 3--4-fold by pretreatment with piperonyl butoxide. These studies support the view that naphthalene-induced pulmonary damage is mediated by the cytochrome P-450-dependent metabolism of naphthalene and that glutathione plays an important role in the detoxification of the lung damaging metabolite(s).
D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009281:Naphthalenes / Q000009:adverse effects / Q000378:metabolism*; D009336:Necrosis; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D014018:Tissue Distribution
D008298:Maleates; D009281:Naphthalenes; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C014476:diethyl maleate; D005978:Glutathione; D010882:Piperonyl Butoxide