Abstract
A systematic study with phase 1 and phase 2 metabolites of cholesterol and vitamin D was conducted to determine whether their biological activity is mediated by the vitamin D receptor (VDR). The investigation necessitated the development of novel synthetic routes for lithocholic acid (LCA) glucuronides (Gluc). Biochemical and cell-based assays were used to demonstrate that hydroxylated LCA analogs were not able to bind VDR. This excludes VDR from mediating their biological and pharmacological activities. Among the synthesized LCA conjugates a novel VDR agonist was identified. LCA Gluc II increased the expression of CYP24A1 in DU145 cancer cells especially in the presence of the endogenous VDR ligand 1,25(OH)2D3. Furthermore, the methyl ester of LCA was identified as novel VDR antagonist. For the first time, we showed that calcitroic acid, the assumed inactive final metabolite of vitamin D, was able to activate VDR-mediated transcription to a higher magnitude than bile acid LCA. Due to a higher metabolic stability in comparison to vitamin D, a very low toxicity, and high concentration in bile and intestine, calcitroic acid is likely to be an important mediator of the protective vitamin D properties against colon cancer.
References
Sep 4, 1979·Biochemistry·R P EsveltH F DeLuca
Jul 1, 1973·Gut·T C Northfield, I McColl
Feb 1, 1984·Journal of Steroid Biochemistry·S IshizukaA W Norman
Jul 1, 1994·Chemical & Pharmaceutical Bulletin·T IidaT Nambara
Dec 15, 1995·Cell·D J MangelsdorfR M Evans
Mar 11, 2000·Molecular Cell·N RochelD Moras
Sep 30, 2000·European Journal of Biochemistry·T SakakiK Inouye
May 23, 2002·Science·Makoto MakishimaDavid J Mangelsdorf
Jan 25, 2003·Annual Review of Biochemistry·David W Russell
Aug 10, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Hannah JacksonJoe West
Jan 9, 2008·Journal of Lipid Research·Michiyasu IshizawaMakoto Makishima
Feb 3, 2009·Biochemistry·Arnaud TeichertDaniel D Bikle
May 9, 2012·Journal of Medicinal Chemistry·Premchendar NandhikondaLeggy A Arnold
Jun 1, 2013·Journal of Lipid Research·Hiroyuki MasunoNobutoshi Ito
Dec 18, 2013·Journal of Lipid Research·Jie ChengFrank J Gonzalez
Mar 13, 2014·Journal of the European Academy of Dermatology and Venereology : JEADV·B AscherB Havlickova
Citations
Apr 29, 2016·Journal of Cellular Biochemistry·Elżbieta Gocek, George P Studzinski
Oct 22, 2016·ACS Chemical Biology·Olivia B Yu, Leggy A Arnold
Sep 28, 2020·Analytica Chimica Acta·Miao LinJin-Lan Zhang
Aug 22, 2017·ACS Combinatorial Science·Kelly A TeskeLeggy A Arnold