The effect of Nrf2 knockout on the constitutive expression of drug metabolizing enzymes and transporters in C57Bl/6 mice livers

Abstract

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.