Vol. 61, Issue 3, 507-515, March 2002

Regulation of Pulmonary and Hepatic Cytochrome P4501A Expression in the Rat by Hyperoxia: Implications for Hyperoxic Lung Injury

Xanthi I. Couroucli, Stephen E. Welty, Robert S. Geske, and Bhagavatula Moorthy

Department of Pediatrics, University of Texas-Houston Medical School, Houston, Texas (X.I.C.); Department of Pediatrics, The Ohio State University, Columbus, Ohio (S.E.W.); and Department of Pediatrics, Baylor College of Medicine, Houston, Texas (R.S.G., B.M.)

Supplemental oxygen therapy is frequently used in the treatment of pulmonary insufficiency, as is encountered in premature infants, and in patients with acute respiratory distress syndrome. However, hyperoxia causes lung damage in experimental animals and may do so in humans. Cytochrome P4501A enzymes have been implicated in hyperoxic lung injury. In this study, we investigated the mechanisms of CYP1A1 regulation by hyperoxia and tested the hypothesis that aryl hydrocarbon receptor (AHR)-dependent mechanisms contribute to induction of CYP1A1 and that modulation of CYP1A by hyperoxia may have implications for lung injury. Exposure of adult male Sprague-Dawley rats to hyperoxia for 24 to 48 h led to increased expression of pulmonary CYP1A1 enzyme, which was preceded by enhancement of the corresponding mRNA, followed by decline of induction at 60 h, when the animals displayed severe respiratory distress and lung inflammation. Similarly, hepatic CYP1A1/1A2 mRNAs were markedly induced between 24 and 48 h of hyperoxia, with induction declining by 60 h. Electrophoretic mobility shift assays (EMSA) and experiments with AHR (/) mice indicated that AHR-dependent mechanisms contributed to CYP1A induction. The AHR (/) mice were refractory to CYP1A1 induction by hyperoxia and were more sensitive to lung injury than wild-type mice. Lungs of hyperoxic rats showed increase in the expression of CYP1A1 in airway epithelial cells, type II pneumocytes, and endothelial cells. In conclusion, our results suggest that induction of CYP1A1 by hyperoxia is mediated by AHR-dependent mechanisms and that modulation of CYP1A enzymes by hyperoxia may have implications for hyperoxic lung injury.