Augmented oxygen-mediated transcriptional activation of cytochrome P450 (CYP)1A expression and increased susceptibilities to hyperoxic lung injury in transgenic mice carrying the human CYP1A1 or mouse 1A2 promoter in vivo

Abstract

Supplemental oxygen administration is frequently administered to preterm and term infants having pulmonary insufficiency. However, hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Cytochrome P450 (CYP)A enzymes have been implicated in hyperoxic lung injury. In this study, we tested the hypothesis that hyperoxia induces CYP1A1 and 1A2 enzymes by transcriptional activation of the corresponding promoters in vivo, and transgenic mice expressing the human CYP1A1 or the mouse 1A2 promoter would be more susceptible to hyperoxic lung injury than wild type (WT) mice. Adult WT (CD-1) (12 week-old) mice, transgenic mice carrying a 10 kb human CYP1A1 promoter and the luciferase (luc) reporter gene (CYP1A1-luc), or mice expressing the mouse CYP1A2 promoter (CYP1A2-luc) were maintained in room air or exposed to hyperoxia for 24–72 h. Hyperoxia exposure of CYP1A1-luc mice for 24 and 48 h resulted in 2.5- and 1.25-fold increases, respectively in signal intensities, compared to room air controls. By 72 h, the induction had declined to control levels. CYP1A2-luc mice also showed enhanced luc expression after 24–48 h, albeit to a lesser extent than those expressing the CYP1A1 promoter. Also, these mice showed decreased levels of endogenous CYP1A1 and 1A2 expression after prolonged hyperoxia, and were also more susceptible to lung injury than similarly exposed WT mice, with CYP1A2-luc mice showing the greatest injury. Our results support the hypothesis that hyperoxia induces CYP1A enzymes by transcriptional activation of its corresponding promoters, and that decreased endogenous expression of these enzymes contribute to the increased susceptibilities to hyperoxic lung injury in the transgenic animals. In summary, this is the first report providing direct evidence of hyperoxia-mediated induction of CYP1A1 and CYP1A2 expression in vivo by mechanisms entailing transcriptional activation of the corresponding promoters, a phenomenon that has implications for hyperoxic lung injury, as well as other pathologies caused by oxidative stress.

Coenzyme Q1as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type andNqo1-null mouse lung

“…CoQ 1 and CoQ 1 H 2 have been reported to undergo phase I and II reactions, respectively, and cytochrome P-450 1A expression is increased in the hyperoxiaexposed mouse lung (8,15,33). However, the present study ruled out such irreversible hydroxylation or conjugation reactions as explanations for the difference between CoQ 1 redox metabolism in room air-and hyperoxia-exposed lungs.…”

Bone Marrow Injury Induced via Oxidative Stress in Mice by Inhalation Exposure to Formaldehyde

“…Oxidative stress can induce protective or adverse cellular responses in a dose-dependent manner. CYP1A1 is a phase I metabolic enzyme that plays an important role in the production of ROS during the metabolism of numerous exogenous and endogenous compounds [41], [42]. Lower oxidative stress level induces cytoprotective responses, phase II drug metabolizing enzymes and antioxidant, such as GSTT1 and GSH, are involved in the elimination of ROS [43], [44].…”

Oxidative Stress and Therapeutic Development in Lung Diseases

“…Some of the major enzymatic sources of ROS and RNS include flavoproteins that produce H 2 O 2 , and xanthine oxidase and the nitric oxide synthases that produce O 2 •− and NO • [ 3 – 5 ]. A number of other important cellular enzymes such as Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase, lipooxygenases, uncoupled endothelial nitric oxide synthase (eNOS), and cytochrome P450, contribute to the production of ROS/RNS that play a role in lung diseases [ 6 – 9 ]. Non-enzymatic production of reactive species also occurs through metal-catalyzed oxidation such as the Fenton reaction (Fe 2+ + H 2 O 2 → Fe 3+ + OH − + OH • ) or thermodynamic reactions of NO • with O 2 •− to form peroxynitrite (ONOO − ) [ 10 , 11 ].…”