Synthesis and evaluation of vitamin D receptor-mediated activities of cholesterol and vitamin D metabolites

Autor: Jonathan W. Bogart, Daniel D. Bikle, Joshua Preston, Leggy A. Arnold, James M. Cook, Kelly A. Teske, Nicholas R. Silvaggi, Luis M. Sanchez, Olivia B. Yu
Rok vydání: 2016
Předmět:
Male
25(OH)(2)D-3
0301 basic medicine
Calcitroic acid
Transcription
Genetic
Metabolite
Calcitriol receptor
chemistry.chemical_compound
0302 clinical medicine
Receptors
Drug Discovery
Metabolites
Vitamin D
Vitamin D3 24-Hydroxylase
Cancer
Tumor
Bile acid
Lithocholic acid
Pharmacology and Pharmaceutical Sciences
General Medicine
Cholesterol
Biochemistry
030220 oncology & carcinogenesis
Lithocholic Acid
lipids (amino acids
peptides
and proteins)
Transcription
medicine.drug_class
Medicinal & Biomolecular Chemistry
Glucuronates
DU145
Article
Cell Line
Medicinal and Biomolecular Chemistry
03 medical and health sciences
Mediator
Calcitriol
Genetic
CYP24A1
Cell Line
Tumor
medicine
Vitamin D and neurology
Humans
Nutrition
Pharmacology
Organic Chemistry
Prostatic Neoplasms
030104 developmental biology
chemistry
Vitamin D receptor
Receptors
Calcitriol
Digestive Diseases
Zdroj: European Journal of Medicinal Chemistry. 109:238-246
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2016.01.002
Popis: 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.
Databáze: OpenAIRE
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