The effect of Nrf2 knockout on the constitutive ex
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 tran- scription 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 andro- stane receptor (CAR), and pregnane X receptor (PXR) at mRNA, and protein ex
Ó 2011 Elsevier Ltd. All rights reserved.
Humans and higher organisms are simultaneously exposed to different natural and synthetic xenobiotics through the intake of air, water, and food. Therefore, their ability to withstand toxic chemical insults and oxidative stress through a wide array of enzy- matic defense systems has become a necessity for survival (Chanas et al., 2002). The biotransformation and detoxification processes are two sequential reactions that involve phase I and phase II drug metabolizing enzymes, respectively. In phase I reactions, xenobiot- ics are mainly oxidized by cytochrome P450s (CYPs) to become more polar metabolites. Consequently, phase II reactions, facili- tated by key enzymes such as NAD(P)H: quinone oxidoreductase- 1 (Nqo1), glutathione-S-transferases (Gsts), and UDP-glu- curonosyltransferases (UGTs) convert reactive phase I metabolites
into more hydrophilic secondary metabolites (Nebert and Duffy, 1997).
It is well documented that different families of CYPs participate in the oxidative metabolism of endo- and xenobiotic substrates (Ramana and Kohli, 1998). Importantly, only the mammalian CYP1, 2, and 3 families are known to be involved in the metabolism of xenobiotics through different signaling pathways (Ramana and Kohli, 1998). In general, transcriptional activation of most CYPs oc- curs through three main nuclear receptor mechanisms: the aryl hydrocarbon receptor (AhR) for CYP1 family, the constitutive androstane receptor (CAR) for the CYP2 family; and the pregnane X receptor (PXR) for the CYP3 family (Ramana and Kohli, 1998). Similarly, the phase II metabolizing enzymes are regulated through one of the most versatile mechanisms that involve the antioxidant response element (ARE). This element was first discovered because of its vital role in regulating the inducible levels of rat GSTA2, and NQO1 gene ex
0887-2333/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tiv.2011.01.014
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Toxicology in Vitro
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© Copyright 2017 Anwar Mohamed