Thibeault D W, Downing G, Reddy N, Sonderfan A J, Parkinson A
Department of Neonatology, University of Missouri-Kansas City School of Medicine.
J Pharmacol Exp Ther. 1991 Oct;259(1):444-51.
Treatment of newborn lambs with the cytochrome P-450 (P-450) inhibitor cimetidine and treatment of adult rats with P-450 inducer 3-methylcholanthrene have been reported to provide protection against oxygen-induced lung damage. Cimetidine (30 or 100 mg/kg/day) and 3-methylcholanthrene (25 mg/kg on days 1 and 2) were tested for their ability to protect newborn rats from the acute and chronic lung disease that follows exposure to 100% oxygen. Half of the rats in each group was exposed to 100% oxygen for 8 days; the other half was maintained in room air. Pulmonary microsomes from 1- to 8-day-old rats contained low levels of total cytochrome P-450 and P-450 IIB1, but undetectable levels of P-450 IA1. Exposure to 100% oxygen and/or treatment with cimetidine had no significant effect on P-450 levels, whereas treatment with 3-methylcholanthrene markedly induced IA1. Survival in 100% oxygen was not affected by cimetidine treatment, but was significantly decreased by 3-methylcholanthrene treatment. At 60 days of age, those rats that survived neonatal exposure to 100% oxygen had elevated right ventricular systolic pressure, increased muscularization of arterioles, and enlarged and irregular alveoli, regardless of the neonatal treatment. These results indicate that 3-methylcholanthrene potentiated the toxic effects of oxygen in newborn rats, in contrast to the protective effect reported for adult rats, whereas cimetidine had no discernable effect on oxygen-induced lung toxicity, in contrast to the protective effect reported for newborn lambs. The induction of cytochrome P-450 IA1 by 3-methylcholanthrene may be important in potentiating the toxic effects of oxygen in the neonatal rat lung.
据报道，用细胞色素P - 450（P - 450）抑制剂西咪替丁治疗新生羔羊以及用P - 450诱导剂3 - 甲基胆蒽治疗成年大鼠可预防氧诱导的肺损伤。测试了西咪替丁（30或100毫克/千克/天）和3 - 甲基胆蒽（第1天和第2天为25毫克/千克）保护新生大鼠免受暴露于100%氧气后发生的急性和慢性肺部疾病的能力。每组一半的大鼠暴露于100%氧气中8天；另一半置于室内空气中。1至8日龄大鼠的肺微粒体中总细胞色素P - 450和P - 450 IIB1水平较低，但未检测到P - 450 IA1水平。暴露于100%氧气和/或用西咪替丁治疗对P - 450水平无显著影响，而用3 - 甲基胆蒽治疗则显著诱导IA1。在100%氧气环境中的存活率不受西咪替丁治疗的影响，但3 - 甲基胆蒽治疗使其显著降低。在60日龄时，那些在新生儿期暴露于100%氧气中存活下来的大鼠，无论新生儿期的治疗如何，均出现右心室收缩压升高、小动脉肌化增加以及肺泡增大和不规则。这些结果表明，与报道的成年大鼠的保护作用相反，3 - 甲基胆蒽增强了新生大鼠中氧气的毒性作用；而与报道的新生羔羊的保护作用相反，西咪替丁对氧诱导的肺毒性没有明显影响。3 - 甲基胆蒽诱导细胞色素P - 450 IA1可能在增强新生大鼠肺中氧气的毒性作用方面起重要作用。
