Relationship of cytochrome P-450 activity to Clara cell cytotoxicity. I. Histopathologic comparison of the respiratory tract of mice, rats and hamsters after parenteral administration of naphthalene

Charles Plopper, C. Suverkropp, D. Morin, S. Nishio, Alan R Buckpitt

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The purpose of this study was to define the sites of cytotoxicity within the respiratory tract (nasal cavity and tracheobronchial airway tree) resulting from administration of naphthalene, an organic chemical whose cytotoxic properties require metabolic activation via the cytochrome P-450 monooxygenase system. Three species were compared: mouse, hamster and rat. Naphthalene was administered in corn oil at these doses: mouse (0-400 mg/kg), hamster (0-800 mg/kg) and rat (0-1600 mg/kg), and the animals were sacrificed 24 hr later. In mice, naphthalene produced Clara cell cytotoxicity at 50 mg/kg. The primary alteration was swelling and vacuolation of Clara cells in terminal bronchioles. At 100 mg/kg, the number of terminal bronchioles with vacuolated Clara cells and the number of Clara cells within terminal bronchioles which showed vacuolation increased. At 200 and 300 mg/kg, almost all of the nonciliated cells lining terminal bronchioles in mice were exfoliated and necrotic. In contrast, there was no apparent effect on Clara cells or ciliated cells of terminal bronchioles in rats treated with up to 1600 mg/kg. At 800 mg/kg, minor alterations in Clara cells in some terminal bronchioles were observed in hamsters. At 300 mg/kg, lobar bronchus and trachea showed swelling 'and vacuolation of non-ciliated cells in mice, but no detectable change at 200 mg/kg or below. The trachea and lobar bronchus were unaffected in rats, but showed cytotoxic changes in hamsters. In the nasal cavity of mice, cytotoxicity was observed only in the olfactory epithelium and only in animals treated with 400 mg/kg. There were minimal alterations in the respiratory epithelium. The only epithelial population showing cytotoxicity in the rat was the olfactory epithelium. Complete necrosis was observed at 200 mg/kg and higher. In the hamster there was no discernible alteration in the olfactory epithelium at 100 and 200 mg/kg. At 400 mg/kg, the olfactory epithelium was necrotic. Naphthalene injury to the tracheobronchial epithelium of the mouse is: 1) Clara cell specific; 2) dose- related in the terminal bronchiole; and 3) involves more proximal airways in a dose-dependent fashion. The tracheobronchial epithelium of the rat is refractory to Clara cell injury even at the LD50, but proximal airways are more susceptible than distal airways in the hamster. The nasal cavity shows specific injury in one zone (olfactory epithelium) in a dose and species specific manner. The susceptibility to naphthalene-induced injury in the olfactory epithelium does not correlate with the susceptibility of Clara cells in more distal portions of the respiratory tract. These differences in susceptibility correlate with the rate and stereo-selectivity of naphthalene epoxidation via the cytochrome P-450 system in the nasal cavity and lungs.

Original languageEnglish (US)
Pages (from-to)353-363
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1992

ASJC Scopus subject areas

  • Pharmacology


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