Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1-aminobenzotriazole.
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.
Moorthy
B
B
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. bmoorthy@neo.bcm.tmc.edu
Parker
K M
KM
Smith
C V
CV
Bend
J R
JR
Welty
S E
SE
D000818:Animals; D015153:Blotting, Western; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018496:Hyperoxia / Q000401:mortality / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010078:Oxazines / Q000493:pharmacokinetics; D010100:Oxygen / Q000633:toxicity*; D010996:Pleural Effusion; D020033:Protein Isoforms / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000401:mortality; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010078:Oxazines; D020033:Protein Isoforms; D014230:Triazoles; C067013:N-benzyl-1-aminobenzotriazole; C033020:1-aminobenzotriazole; C044943:pentoxyresorufin; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D010100:Oxygen