title: Synthesis and evaluation of vitamin D receptor-mediated activities of cholesterol and vitamin D metabolites.
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.
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Teske
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Jonathon W
authors.initials: JW
authors.lastname: Bogart
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Sanchez
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Olivia B
authors.initials: OB
authors.lastname: Yu
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Joshua V
authors.initials: JV
authors.lastname: Preston
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Silvaggi
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.affiliation: Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Milwaukee, WI, 53211, United States. Electronic address: arnold2@uwm.edu.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D005965:Glucuronates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008095:Lithocholic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism
chemical_list: D005965:Glucuronates; D018167:Receptors, Calcitriol; D014807:Vitamin D; D008095:Lithocholic Acid; C041558:lithocholate 3-O-glucuronide; D002784:Cholesterol; D065668:Vitamin D3 24-Hydroxylase; C021640:calcitroic acid; D002117:Calcitriol
keywords: 1,25(OH)(2)D(3); CYP24A1; Calcitroic acid; DU145; Lithocholic acid; Metabolites; Vitamin D receptor