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.
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