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3β-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3α-epimer by hepatic metabolism.
Metadata
Journaljournal of steroid biochemistry and molecular biology3.813Date
2020 Jun 04
4 months ago
Type
Journal Article
Volume
2020-Sep / 202 : 105702
Author
Stefela A 1, Kaspar M 2, Drastik M 3, Holas O 4, Hroch M 5, Smutny T 1, Skoda J 1, Hutníková M 1, Pandey AV 6, Micuda S 7, Kudova E 8, Pavek P 9
Affiliation
  • 2. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic; Faculty of Sciences, Charles University in Prague, Albertov 6, Prague 2, 128 43, Czech Republic.
  • 3. Department of Physical Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
  • 4. Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
  • 5. Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870/13, Hradec Kralove, 500 03, Czech Republic.
  • 6. Pediatric Endocrinology, University Children's Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland.
  • 7. Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870/13, Hradec Kralove, 500 03, Czech Republic.
  • 8. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
  • 9. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic. Electronic address: [email protected]
Doi
PMIDMESH
Abstract
Bile acids (BAs) are important signaling molecules acting via the farnesoid X nuclear receptor (FXR) and the membrane G protein-coupled bile acid receptor 1 (GPBAR1). Besides deconjugation of BAs, the oxidoreductive enzymes of colonic bacteria and hepatocytes enable the conversion of BAs into their epimers or dehydrogenated forms. Obeticholic acid (OCA) is the first-in-class BA-derived FXR agonist approved for the treatment of primary biliary cholangitis. Herein, a library of OCA derivatives, including 7-keto, 6-ethylidene derivatives and 3β-epimers, was synthetized and investigated in terms of interactions with FXR and GPBAR1 in transaction assays and evaluated for FXR target genes expression in human hepatocytes and C57BL/6 mice. The derivatives were further subjected to cell-free analysis employing in silico molecular docking and a TR-FRET assay. The conversion of the 3βhydroxy epimer and its pharmacokinetics in mice were studied using LC-MS. We found that only the 3β-hydroxy epimer of OCA (3β-isoOCA) possesses significant activity to FXR in hepatic cells and mice. However, in a cell-free assay, 3β-isoOCA had about 9-times lower affinity to FXR than did OCA. We observed that 3β-isoOCA readily epimerizes to OCA in hepatocytes and murine liver. This conversion was significantly inhibited by the hydroxy-Δ5-steroid dehydrogenase inhibitor trilostane. In addition, we found that 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. We conclude that 3β-isoOCA significantly activates FXR due to its epimerization to the more active OCA by hepatic metabolism. Other modifications as well as epimerization on the C3/C7 positions and the introduction of 6-ethylidene in the CDCA scaffold abrogate FXR agonism and alleviate GPBAR1 activation.
Keywords: Bile acids Gene regulation Metabolism Nuclear receptors Pharmacokinetics
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J Steroid Biochem Mol Bioljournal of steroid biochemistry and molecular biology
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LocationEngland
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