Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Toxicol In Vitro. 2011 Jun;25(4):785-95. doi: 10.1016/j.tiv.2011.01.014. Epub 2011 Jan 31.
Previous reports have proposed a cross-talk between the nuclear factor erythroid-2 p45-related factor-2 (Nrf2)/antioxidant response element (ARE) and the aryl hydrocarbon receptor (AhR)/xenobiotic response element (XRE) signaling pathways. Therefore, the aim of the current study was to examine the level of phase I, phase II drug metabolizing enzymes (DMEs), and phase III transporters and their related transcription factors in the Nrf2 knockout model. Our results showed that phase II DMEs that are under the control of Nrf2 typified by NAD(P)H: quinone oxidoreductase 1 (Nqo1), and glutathione S-transferase (Gst) were significantly lower at the mRNA, protein, and catalytic activity levels in the livers of Nrf2 knockout mice compared to wild type. Furthermore, phase I cytochrome P450s (CYPs), Cyp1, and Cyp2b10 at mRNA, protein, and catalytic activity levels were significantly lower in the livers of Nrf2 knockout mice. Interestingly, our results showed that the transcription factors AhR, constitutive androstane receptor (CAR), and pregnane X receptor (PXR) at mRNA, and protein expression levels were significantly lower in the livers of Nrf2 knockout mice compared to wild type. Importantly, phase III drug transporters mRNA levels of the multiple drug resistance associated proteins (Mrp2 and Mrp3), and solute carrier organic anion transporters (Slco1a6 and Slco2b1) were significantly lower in the liver of Nrf2 knockout mice. Co-activators, Ncoa1, Ncoa2, and Ncoa3 mRNA levels were not altered while co-repressors, Ncor1 and Ncor2 were significantly lower in the livers of Nrf2 knockout mice. In conclusion, knockout of Nrf2 causes disruption to the coordination of phase I, phase II drug DMEs, and phase III drug transporters through altering the transcription factors controlling them.
先前的报告提出核因子红细胞 2 p45 相关因子 2（Nrf2）/抗氧化反应元件（ARE）和芳香烃受体（AhR）/外源性反应元件（XRE）信号通路之间存在串扰。因此，本研究旨在检测 Nrf2 敲除模型中 I 相、II 相药物代谢酶（DME）和 III 相转运体及其相关转录因子的水平。我们的结果表明，受 Nrf2 调控的 II 相 DME，如 NAD（P）H：醌氧化还原酶 1（Nqo1）和谷胱甘肽 S-转移酶（Gst），在 Nrf2 敲除小鼠肝脏中的 mRNA、蛋白和催化活性水平均显著低于野生型。此外，I 相细胞色素 P450s（CYPs）、Cyp1 和 Cyp2b10 的 mRNA、蛋白和催化活性水平在 Nrf2 敲除小鼠肝脏中也显著降低。有趣的是，我们的结果表明，Nrf2 敲除小鼠肝脏中的转录因子 AhR、组成型雄烷受体（CAR）和孕烷 X 受体（PXR）的 mRNA 和蛋白表达水平均显著低于野生型。重要的是，Nrf2 敲除小鼠肝脏中多药耐药相关蛋白（Mrp2 和 Mrp3）和溶质载体有机阴离子转运体（Slco1a6 和 Slco2b1）的 III 相药物转运体 mRNA 水平显著降低。共激活因子 Ncoa1、Ncoa2 和 Ncoa3 的 mRNA 水平没有改变，而 Ncor1 和 Ncor2 的共抑制因子在 Nrf2 敲除小鼠肝脏中显著降低。总之，Nrf2 的敲除通过改变控制它们的转录因子，导致 I 相、II 相药物 DMEs 和 III 相药物转运体的协调紊乱。
