title: Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury.
abstract: Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2(-/-) mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24-72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2(-/-) mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde- and 4-hydroxynonenal-protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Lihua
authors: L
authors: Wang
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Krithika
authors: K
authors: Lingappan
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Weiwu
authors: W
authors: Jiang
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Xanthi I
authors: XI
authors: Couroucli
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Stephen E
authors: SE
authors: Welty
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Binoy
authors: B
authors: Shivanna
authors: Department of Pathology, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors: Roberto
authors: R
authors: Barrios
authors: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Gangduo
authors: G
authors: Wang
authors: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: M
authors: M
authors: Firoze Khan
authors: Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
authors: L
authors: L
authors: Jackson Roberts
authors: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bmoorthy@bcm.edu.
authors: Bhagavatula
authors: B
authors: Moorthy
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D028441:F2-Isoprostanes / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007958:Leukocyte Count; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism; D055370:Lung Injury / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils; D018384:Oxidative Stress / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D028441:F2-Isoprostanes; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D015237:Dinoprost; D019388:Cytochrome P-450 CYP1A2; C027576:4-hydroxy-2-nonenal
keywords: ARDS; Acute lung injury; CYP1A2; Free radicals; Oxidative stress