Oxygen-induced lung damage in newborn rats, potentiated by 3-methylcholanthrene, a P-450 inducer, and lack of protection by cimetidine, a P-450 inhibitor.
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.
Department of Neonatology, University of Missouri-Kansas City School of Medicine.
D W
DW
Thibeault
G
G
Downing
N
N
Reddy
A J
AJ
Sonderfan
A
A
Parkinson
D000818:Animals; D000831:Animals, Newborn; D002927:Cimetidine / Q000097:blood / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D010100:Oxygen / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D008748:Methylcholanthrene; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D010100:Oxygen