title: Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czechia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carazo
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czechia.
authors.forename: Lucie
authors.initials: L
authors.lastname: Hyrsova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czechia.
authors.forename: Jan
authors.initials: J
authors.lastname: Dusek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo náměstí 2, CZ160 00 Praha, Czechia.
authors.forename: Hana
authors.initials: H
authors.lastname: Chodounska
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czechia.
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Horvatova
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Palacky University in Olomouc, 17. listopadu 1131, Olomouc CZ779 00, Czechia.
authors.forename: Karel
authors.initials: K
authors.lastname: Berka
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Palacky University in Olomouc, 17. listopadu 1131, Olomouc CZ779 00, Czechia.
authors.forename: Vaclav
authors.initials: V
authors.lastname: Bazgier
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, Im Neuenheimer Feld, Heidelberg, Germany.
authors.forename: Hongying
authors.initials: H
authors.lastname: Gan-Schreier
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, Im Neuenheimer Feld, Heidelberg, Germany.
authors.forename: Waleé
authors.initials: W
authors.lastname: Chamulitrat
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo náměstí 2, CZ160 00 Praha, Czechia.
authors.forename: Eva
authors.initials: E
authors.lastname: Kudova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czechia. Electronic address: petr.pavek@faf.cuni.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000107:Acetylation; D000818:Animals; D018929:Cell Culture Techniques; D019826:Cholic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003840:Deoxycholic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D010957:Plasmids; D000077297:Pregnane X Receptor; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019826:Cholic Acid; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003840:Deoxycholic Acid; D008024:Ligands; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D000099150:Receptor, Farnesoid X-Activated
keywords: Bile acids; FXR; Metabolism; Nuclear receptors; PXR