title: Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia.
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.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Ishizawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Matsunawa
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Uno
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuno
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced / Q000378:metabolism; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D018167:Receptors, Calcitriol; D008095:Lithocholic Acid