Recent studies have implicated the involvement of cytochrome P450 (CYP) enzymes in the development of hyperoxic lung injury. In the current investigation, we tested the hypothesis that exposure of rats to the CYP inhibitor 1-aminobenzotriazole (ABT) would protect animals from oxygen-induced lung injury. We treated male Sprague-Dawley rats with ABT (65 μmol/kg) dissolved in saline (2 ml/kg) or with equal volumes of saline (2 ml/kg), followed by exposure of the rats to >95% oxygen for 48 or 60 h. Pleural effusion (PE) volumes and lung microsomal ethoxyresorufin O-deethylase (EROD) activities were determined as estimates of lung injury and CYP1A1 activity, respectively. Saline-treated animals exposed to hyperoxia displayed no mortality through 60 h, and at 48 h showed no measurable increases in PE volumes. In contrast, 2/3 ABT-treated rats exposed to hyperoxia for 48 h had PE, and 0/4 survived to 60 h. Saline treated animals exposed to >95% oxygen for 48 h showed 6.2-fold greater lung microsomal EROD activities than did saline-treated air-breathing controls. However, by 60 h the EROD activities in the hyperoxia-exposed animals declined dramatically to control levels. In contrast, lung microsomal EROD activities did not increase in ABT-treated rats following exposure to hyperoxia for 48 h. In conclusion the results of these studies suggest that induction of CYP1A1 may be a significant adaptive response to hyperoxia. Supported in part by NIH GM44263 and by NIH 5 P30 HD27823