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Vol. 292, Issue 2, 553-560, February 2000

Potentiation of Oxygen-Induced Lung Injury in Rats by the Mechanism-Based Cytochrome P-450 Inhibitor, 1-Aminobenzotriazole1

Bhagavatula Moorthy, Kristen M. Parker, Charles V. Smith, John R. Bend and Stephen E. Welty

Department of Pediatrics, Baylor College of Medicine (B.M., K.M.P., C.V.S., S.E.W.), Houston, Texas; and Department of Pharmacology and Toxicology, University of Western Ontario (J.R.B.), London, Ontario.

In this investigation, we tested the hypothesis that the cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) alters the susceptibility of rats to hyperoxic lung injury. Male Sprague-Dawley rats were treated i.p. with ABT (66 mg/kg), i.v. with N-benzyl-1-aminobenzotriazole (1 µmol/kg), or the respective vehicles, followed by exposure to >95% oxygen for 24, 48, or 60 h. Pleural effusion volumes were measured as estimates of hyperoxic lung injury, and lung microsomal ethoxyresorufin O-deethylation (EROD) (CYP1A1) activities and CYP1A1 apoprotein levels were determined by Western blotting. ABT-pretreated animals exposed to hyperoxia died between 48 and 60 h, whereas no deaths were observed with up to 60 h of hyperoxia in vehicle-treated animals. In addition, three of four ABT-treated rats exposed to hyperoxia for 48 h showed marked pleural effusions. Exposure of vehicle-treated rats to hyperoxia led to 6.3-fold greater lung EROD activities and greater CYP1A1 apoprotein levels than in air-breathing controls after 48 h, but both declined to control levels by 60 h. Liver CYP1A1/1A2 enzymes displayed responses to hyperoxia and ABT similar to the effects on lung CYP1A1. N-Benzyl-1-aminobenzotriazole markedly inhibited lung microsomal pentoxyresorufin O-depentylation (principally CYP2B1) activities in air-breathing and hyperoxic animals but did not affect lung EROD or liver CYP activities. In conclusion, the results suggest that induction of CYP1A enzymes may serve as an adaptive response to hyperoxia, and that CYP2B1, the major pulmonary CYP isoform, does not contribute significantly to hyperoxic lung injury.

1 This work was supported in part by U.S. Public Health Service Grants ES09132 and GM44263 awarded by the National Institute of Environmental Health Sciences and the National Institutes of General Medical Sciences, respectively, and by a research grant awarded by the American Lung Association of Texas, and by Medical Research Council of Canada Grant MT-9722 (to J.R.B.).

0022-3565/00/2922-0553$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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