Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands*

By L. Moore, D. Parks, Stacey A. Jones, R. Bledsoe, T. Consler, J. Stimmel, B. Goodwin, C. Liddle, S. Blanchard, T. Willson and 2 more. Journal of Biological Chemistry, 2000

849 citations recorded by the source corpus.

Xenobiotics induce the transcription of cytochromes P450 (CYPs) 2B and 3A through the constitutive androstane receptor (CAR; NR1I3) and pregnane X receptor (PXR; NR1I2), respectively. In this report, we have systematically compared a series of xenobiotics and natural steroids for their effects on mouse and human CAR and PXR. Our results demonstrate dual regulation of PXR and CAR by a subset of compounds that affect CYP expression. Moreover, there are marked pharmacological differences between the mouse (m) and human (h) orthologs of both CAR and PXR. For example, the planar hydrocarbon 1,4-bis[2-(3,5-dichloropyridyl-oxy)]benzene activates mCAR and hPXR but has little or no activity on hCAR and mPXR. In contrast, the CAR deactivator androstanol activates both mouse and human PXR. Similarly, the PXR activator clotrimazole is a potent deactivator of hCAR. Using radioligand binding and fluorescence resonance energy transfer assays, we demonstrate that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors. Our results suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds. Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.

Subfields: Genetics, Pharmacology, Surgery

View Paper: https://www.semanticscholar.org/paper/4736efc1d485861ba3c24fa140233023003c5a8d

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Citations in the corpus

The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. (2002, methodology): “A phylogenetic analysis of the NR1I subfamily suggests that CAR and BXR may have evolved from an ancestral receptor through deletion of an exon that removed a segment of the helix 1–helix 3 insert (89).”
Induction of phase I, II and III drug metabolism/transport by xenobiotics (2005, background): “…the signaling mechanism involving the aryl hydrocarbon receptor (AhR) (Hahn, 2002; Rowlands and Gustafsson, 1997), the orphan nuclear receptors (Moore et aL, 2000; Wang and LeCluyse, 2003), and other relevant transcription factors and/or signal transduction cascades (Kumar and Thompson, 1999;…”
Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. (2002, background): “Because both CAR and PXR can be regulated by endogenous substances, such as steroids (Forman et al., 1998; Kliewer et al., 1998; Moore et al., 2000b; Staudinger et al., 2001; Xie et al., 2001), these nuclear receptors may also be important components in the body’s defenses against chemicals that…”
Metabolism and Disposition Kinetics of Nicotine (2005, background): “Kawamoto T, Kakizaki S, Yoshinari K, and Negishi M (2000) Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene.”
Primary Hepatocytes: Current Understanding of the Regulation of Metabolic Enzymes and Transporter Proteins, and Pharmaceutical Practice for the Use of Hepatocytes in Metabolism, Enzyme Induction, Transporter, Clearance, and Hepatotoxicity Studies (2007, background): “…(RXR for both PXR and CAR) and then bind to the target xenobiotic response elements (XRE) located in both the proximal and distal P450 gene promoters, resulting in the transcription of the respective CYP isoform (Goodwin et al., 1999; Lehmann et al., 1998; Moore et al., 2000; Sueyoshi et al.,”
Polymorphism of human cytochrome P450 enzymes and its clinical impact (2009, background): “…been stimulated by the discovery of polymorphic and ethnic differences in CYP2B6 expression (Ariyoshi et al., 2001a; Lang et al., 2001), identification of additional substrates for CYP2B6, and evidence for coregulation with CYP3A4 (Faucette et al., 2004; Goodwin et al., 2001; Moore et al., 2000).”
The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism (2000, background): “However, PB is a better agonist ligand for the related receptor SXR/PXR than for CA”