Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2011 Apr 1;407(1):79-85. doi: 10.1016/j.bbrc.2011.02.113. Epub 2011 Mar 6.
Supplemental oxygen administration is frequently administered to pre-term 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) (12week-old) mice, transgenic mice carrying a 10kb 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 24-72h. Hyperoxia exposure of CYP1A1-luc mice for 24 and 48h resulted in 2.5- and 1.25-fold increases, respectively, in signal intensities, compared to room air controls. By 72h, the induction had declined to control levels. CYP1A2-luc mice also showed enhanced luc expression after 24-48h, 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.
补充氧气常被用于患有肺功能不全的早产儿和足月儿。然而，高氧会导致早产儿支气管肺发育不良（BPD）的发生。细胞色素 P450（CYP）A 酶已被认为与高氧性肺损伤有关。在这项研究中，我们通过体内相应启动子的转录激活来检验高氧诱导 CYP1A1 和 1A2 酶的假设，并且表达人 CYP1A1 或小鼠 1A2 启动子的转基因小鼠比野生型（WT）小鼠更容易发生高氧性肺损伤。成年 WT（CD-1）（12 周龄）小鼠、携带 10kb 人 CYP1A1 启动子和荧光素酶（luc）报告基因（CYP1A1-luc）的转基因小鼠或表达小鼠 CYP1A2 启动子（CYP1A2-luc）的小鼠在室内空气或高氧中维持 24-72 小时。与室内空气对照相比，CYP1A1-luc 小鼠在高氧暴露 24 和 48 小时后，信号强度分别增加了 2.5 倍和 1.25 倍。72 小时后，诱导作用已降至对照水平。CYP1A2-luc 小鼠在 24-48 小时后也表现出增强的 luc 表达，但程度低于表达 CYP1A1 启动子的小鼠。此外，这些小鼠在长时间高氧暴露后表现出内源性 CYP1A1 和 1A2 表达水平降低，并且比类似暴露的 WT 小鼠更容易发生肺损伤，CYP1A2-luc 小鼠表现出最大的损伤。我们的结果支持这样的假设，即高氧通过其相应启动子的转录激活诱导 CYP1A 酶，并且这些酶的内源性表达降低导致转基因动物对高氧性肺损伤的易感性增加。总之，这是第一项提供直接证据的报告，证明体内通过涉及相应启动子转录激活的机制，高氧可诱导 CYP1A1 和 CYP1A2 的表达，这一现象与高氧性肺损伤以及由氧化应激引起的其他病理有关。
