Faculty Collaboration Database

Synthesis and evaluation of vitamin D receptor-mediated activities of cholesterol and vitamin D metabolites. Eur J Med Chem 2016 Feb 15;109:238-46

Date

01/18/2016

Pubmed ID

26774929

Pubmed Central ID

PMC4737989

DOI

10.1016/j.ejmech.2016.01.002

Scopus ID

2-s2.0-84954311265 (requires institutional sign-in at Scopus site)   16 Citations

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.

Author List

Teske KA, Bogart JW, Sanchez LM, Yu OB, Preston JV, Cook JM, Silvaggi NR, Bikle DD, Arnold LA

Authors

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee
Nicholas R. Silvaggi PhD Assistant Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Calcitriol
Cell Line, Tumor
Cholesterol
Glucuronates
Humans
Lithocholic Acid
Male
Prostatic Neoplasms
Receptors, Calcitriol
Transcription, Genetic
Vitamin D
Vitamin D3 24-Hydroxylase