PMID- 15123765 OWN - NLM STAT- MEDLINE DCOM- 20050328 LR - 20201208 IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 310 IP - 2 DP - 2004 Aug TI - Disruption of the Ah receptor gene alters the susceptibility of mice to oxygen-mediated regulation of pulmonary and hepatic cytochromes P4501A expression and exacerbates hyperoxic lung injury. PG - 512-9 AB - Administration of supplemental oxygen is frequently encountered in infants suffering from pulmonary insufficiency and in adults with acute respiratory distress syndrome. However, hyperoxia causes acute lung damage in experimental animals. In the present study, we investigated the roles of the Ah receptor (AHR) in the modulation of cytochrome P4501A (CYP1A) enzymes and in the development of lung injury by hyperoxia. Adult male wild-type [AHR (+/+)] mice and AHR-deficient animals [AHR (-/-)] were maintained in room air or exposed to hyperoxia (>95% oxygen) for 24 to 72 h, and pulmonary and hepatic expression of CYP1A and lung injury were studied. Hyperoxia caused significant increases in pulmonary and hepatic CYP1A1 activities (ethoxyresorufin O-deethylase) and mRNA levels in wild-type (C57BL/6J) AHR (+/+), but not AHR (-/-) mice, suggesting that AHR-dependent mechanisms contributed to CYP1A1 induction. On the other hand, hyperoxia augmented hepatic CYP1A2 expression in both wild-type and AHR (-/-) animals, suggesting that AHR-independent mechanisms contributed to the CYP1A2 regulation by hyperoxia. AHR (-/-) mice exposed to hyperoxia were more susceptible than wild-type mice to lung injury and inflammation, as indicated by significantly higher lung weight/body weight ratios, increased pulmonary edema, and enhanced neutrophil recruitment into the lungs. In conclusion, our results support the hypothesis that the hyperoxia induces CYP1A1, but not CYP1A2, expression in vivo by AHR-dependent mechanisms, a phenomenon that may mechanistically contribute to the beneficial effects of the AHR in hyperoxic lung injury. FAU - Jiang, Weiwu AU - Jiang W AD - Department of Pediatrics, Baylor College of Medicine, 6621 Fannin, FC 530.01, Houston, TX 77030, USA. . bmoorthy@bcm.tmc.edu FAU - Welty, Stephen E AU - Welty SE FAU - Couroucli, Xanthi I AU - Couroucli XI FAU - Barrios, Roberto AU - Barrios R FAU - Kondraganti, Sudha R AU - Kondraganti SR FAU - Muthiah, Kathirvel AU - Muthiah K FAU - Yu, Ling AU - Yu L FAU - Avery, Stephen E AU - Avery SE FAU - Moorthy, Bhagavatula AU - Moorthy B LA - eng GR - K08 HL 04333/HL/NHLBI NIH HHS/United States GR - R01 ES 09132/ES/NIEHS NIH HHS/United States GR - R01 HL 070921/HL/NHLBI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20040503 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Receptors, Aryl Hydrocarbon) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) RN - S88TT14065 (Oxygen) SB - IM MH - Animals MH - Cytochrome P-450 CYP1A1/*biosynthesis/genetics MH - Cytochrome P-450 CYP1A2/*biosynthesis/genetics MH - Gene Expression Regulation, Enzymologic/physiology MH - Genetic Predisposition to Disease/*genetics MH - Liver/enzymology MH - Lung/drug effects/enzymology/*metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Oxygen/*toxicity MH - Receptors, Aryl Hydrocarbon/*deficiency/*genetics/physiology MH - Respiratory Distress Syndrome/enzymology/genetics/*metabolism EDAT- 2004/05/05 05:00 MHDA- 2005/03/29 09:00 CRDT- 2004/05/05 05:00 PHST- 2004/05/05 05:00 [pubmed] PHST- 2005/03/29 09:00 [medline] PHST- 2004/05/05 05:00 [entrez] AID - jpet.103.059766 [pii] AID - 10.1124/jpet.103.059766 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2004 Aug;310(2):512-9. doi: 10.1124/jpet.103.059766. Epub 2004 May 3.