title: Cell-based and in silico evidence against quercetin and structurally-related flavonols as activators of vitamin D receptor.
abstract: It has been reported that quercetin is an activator of rat vitamin D receptor (rVDR). However, the conclusion was based on experiments performed without all the appropriate control groups, raising the possibility of a false-positive finding. Furthermore, distinct differences exist in the chemical structures of quercetin and 1α,25-dihydroxyvitamin D3, which is a prototypic agonist of VDR. Therefore, we investigated systematically whether quercetin and other flavonols are agonists of rVDR, mouse VDR (mVDR), or human VDR (hVDR). Quercetin, 3-hydroxyflavone, galangin, datiscetin, kaempferol, morin, isorhamnetin, tamarixetin, myricetin, and syringetin did not activate rVDR, mVDR, or hVDR in HEK-293 and HepG2 cells transfected with the corresponding receptor expression plasmid and either the secreted phosphoprotein 1 (Spp1) or cytochrome P450 24A1 (CYP24A1) reporter plasmid, when compared to the respective empty vector control group transfected with one or the other reporter plasmid and treated with one of the flavonols. Control analysis indicated that lithocholic acid and 1α,25-dihydroxyvitamin D3, but not rifampicin, activated rVDR, mVDR, and hVDR. As shown in transfected HEK293 and HepG2 cells, the flavonols did not influence hVDR ligand binding domain transactivation, steroid receptor coactivator-1 recruitment, or hVDR target gene expression (transient receptor potential cation channel 6 and CYP24A1) in hVDR-expressing Caco-2 or LS180 cells. The cumulative data from the cell-based experiments were corroborated by results obtained from molecular docking analysis. In conclusion, quercetin, 3-hydroxyflavone, galangin, datiscetin, kaempferol, morin, isorhamnetin, tamarixetin, myricetin, and syringetin are not agonists of rVDR, mVDR, or hVDR, as judged by cell-based and in silico evidence.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia Vancouver, BC V6T 1Z3, Canada.
authors.forename: Aik Jiang
authors.initials: AJ
authors.lastname: Lau
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Politi
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia Vancouver, BC V6T 1Z3, Canada.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia Vancouver, BC V6T 1Z3, Canada. Electronic address: thomas.chang@ubc.ca.
authors.forename: Thomas K H
authors.initials: TK
authors.lastname: Chang
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002117:Calcitriol / Q000494:pharmacology*; D004187:Disaccharides / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D044949:Kaempferols / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology*; D018167:Receptors, Calcitriol / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019076:Transgenes; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism; D047309:Flavones
chemical_list: D002117:Calcitriol; D004187:Disaccharides; D005419:Flavonoids; D044949:Kaempferols; D053495:Osteopontin; D011794:Quercetin; D018167:Receptors, Calcitriol; D065668:Vitamin D3 24-Hydroxylase; C506895:SPP1 protein, human; C579457:VDR protein, human; C546494:syringetin; C047368:3-methylquercetin; C037032:galangin; C006552:kaempferol; C508967:tamarixetin; C040015:myricetin; C008548:morin; D047309:Flavones; C585549:CYP24A1 protein, human; C041477:3-hydroxyflavone
keywords: 3-Hydroxyflavone; CYP24A1; Flavonol; Quercetin; TRPV6; Vitamin D receptor