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.
- MeSH
- acetylace MeSH
- buněčné kultury MeSH
- buňky Hep G2 MeSH
- cytochrom P-450 CYP3A genetika MeSH
- cytochrom P450 CYP2B6 genetika MeSH
- hepatocyty účinky léků enzymologie metabolismus MeSH
- kyselina cholová chemie metabolismus farmakologie MeSH
- kyselina deoxycholová chemie metabolismus farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- myši MeSH
- oxidace-redukce MeSH
- P-glykoprotein genetika MeSH
- plazmidy MeSH
- receptory cytoplazmatické a nukleární chemie genetika metabolismus MeSH
- receptory kalcitriolu chemie genetika metabolismus MeSH
- reportérové geny MeSH
- simulace molekulového dockingu MeSH
- steroidní receptory chemie genetika metabolismus MeSH
- techniky dvojhybridového systému MeSH
- transfekce MeSH
- vazba proteinů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
