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 micromol/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.