Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1-aminobenzotriazole.
Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1-aminobenzotriazole.
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发表时间：
2000-02
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通讯作者：
B. Moorthy;K. M. Parker;Charles V. Smith;J. Bend;S. Welty
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作者：
B. Moorthy;K. M. Parker;Charles V. Smith;J. Bend;S. Welty
在这项研究中，我们测试的假设，细胞色素P-450（CYP）抑制剂1-氨基苯并三唑（ABT）改变大鼠对高氧肺损伤的易感性。雄性Sprague-Dawley大鼠用ABT（66 mg/kg）腹膜内处理，用N-苄基-1-氨基苯并三唑（1 μ mol/kg）静脉内处理，或各自的载体处理，随后暴露于>95%的氧气24、48或60小时。测定胸腔积液量作为高氧肺损伤的估计值，并通过Western印迹法测定肺微粒体乙氧基试卤灵O-脱乙基化（EROD）（CYP 1A 1）活性和CYP 1A 1载脂蛋白水平。ABT预处理的动物暴露于高氧在48和60小时之间死亡，而没有观察到死亡与高达60小时的高氧溶剂处理的动物。此外，四个ABT处理的大鼠暴露于高氧48小时显示出显着的胸腔积液。暴露于高氧的车辆处理的大鼠导致6.3倍以上的肺EROD活动和更大的CYP 1A 1载脂蛋白水平比空气呼吸控制48小时后，但都下降到控制水平的60小时。肝脏CYP 1A 1/1A 2酶对高氧和ABT的反应与对肺CYP 1A 1的影响相似。N-苄基-1-氨基苯并三唑显著抑制呼吸空气和高氧动物的肺微粒体戊氧基试卤灵O-脱戊基化（主要是CYP 2B 1）活性，但不影响肺EROD或肝EROD活性。总之，结果表明，CYP 1A酶的诱导可能是对高氧的适应性反应，而CYP 2B 1，主要的肺动脉高压亚型，对高氧肺损伤没有显着贡献。
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.