Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia.

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Ishizawa M, Matsunawa M, Adachi R, Uno S, Ikeda K, Masuno H, Shimizu M, Iwasaki K, Yamada S, Makishima M

Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia.

J Lipid Res. 2008 Apr;49(4):763-72. doi: 10.1194/jlr.M700293-JLR200. Epub 2008 Jan 7.

PubMed ID

18180267 [ View in PubMed

]

Abstract

1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and also exhibits noncalcemic actions on immunity and cell differentiation. In addition to disorders of bone and calcium metabolism, VDR ligands are potential therapeutic agents in the treatment of immune disorders, microbial infections, and malignancies. Hypercalcemia, the major adverse effect of vitamin D(3) derivatives, limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR, and its synthetic derivative, LCA acetate, is a potent VDR agonist. In this study, we found that an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. LCA acetate and LCA propionate induced the expression of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) as effectively as that of 1alpha,25-dihydroxyvitamin D(3) 24-hydroxylase (CYP24A1), whereas 1,25(OH)(2)D(3) was more effective on TRPV6 than on CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate and LCA propionate effectively induced tissue VDR activation without causing hypercalcemia. These bile acid derivatives have the ability to function as selective VDR modulators.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Chenodeoxycholic acid	G-protein coupled bile acid receptor 1	Protein	Humans	Unknown	Not Available	Details
Cholic Acid	G-protein coupled bile acid receptor 1	Protein	Humans	Unknown	Not Available	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Calcitriol	Approved Nutraceutical	CAMP	820	upregulated	Calcitriol results in increased expression of CAMP mRNA	3p21.31
Calcitriol	Approved Nutraceutical	CD14	929	upregulated	Calcitriol results in increased expression of CD14 mRNA	5q31.3
Calcitriol	Approved Nutraceutical	CYP24A1	1591	upregulated	[Calcitriol binds to and results in increased activity of VDR protein] which results in increased expression of CYP24A1 mRNA	20q13.2
Calcitriol	Approved Nutraceutical	ITGAM	3684	upregulated	Calcitriol results in increased expression of ITGAM mRNA	16p11.2
Calcitriol	Approved Nutraceutical	TRPV6	55503	upregulated	[Calcitriol binds to and results in increased activity of VDR protein] which results in increased expression of TRPV6 mRNA	7q34