Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor

Toxicol Lett. 2017 Jan 4;265:86-96. doi: 10.1016/j.toxlet.2016.11.013. Epub 2016 Nov 18.

Abstract

The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells. We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1. In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments.

Keywords: Bile acids; FXR; Metabolism; Nuclear receptors; PXR.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Acetylation
  • Animals
  • Cell Culture Techniques
  • Cholic Acid / chemistry*
  • Cholic Acid / metabolism
  • Cholic Acid / pharmacology
  • Cytochrome P-450 CYP2B6 / genetics
  • Cytochrome P-450 CYP3A / genetics
  • Deoxycholic Acid / chemistry*
  • Deoxycholic Acid / metabolism
  • Deoxycholic Acid / pharmacology
  • Dose-Response Relationship, Drug
  • Genes, Reporter
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Ligands
  • Mice
  • Molecular Docking Simulation
  • Oxidation-Reduction
  • Plasmids
  • Pregnane X Receptor
  • Protein Binding
  • Receptors, Calcitriol / chemistry
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / chemistry*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Ligands
  • Pregnane X Receptor
  • Receptors, Calcitriol
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Deoxycholic Acid
  • farnesoid X-activated receptor
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Cholic Acid