title: Vitamin D3 derivatives with adamantane or lactone ring side chains are cell type-selective vitamin D receptor modulators.
abstract: The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, which regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. We investigated the effects of three 1,25(OH)(2)D(3) derivatives on VDR function. AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position. These vitamin D derivatives bind to VDR but do not stabilize an active cofactor conformation. In a VDR transfection assay, AD47 and LAC67b act as partial agonists and all three compounds inhibit VDR activation by 1,25(OH)(2)D(3). The derivatives enhanced the heterodimerization of VDR with the retinoid X receptor, an effect unrelated to agonist/antagonist activity. AD47 and LAC67b weakly induced recruitment of the SRC-1 cofactor to VDR, and all three derivatives inhibited the recruitment of p160 family cofactors to VDR induced by 1,25(OH)(2)D(3). It is noteworthy that AD47 induced DRIP205 recruitment as effectively as 1,25(OH)(2)D(3), whereas LAC67a and LAC67b were not effective. We examined the expression of endogenous VDR target genes and the nuclear protein levels of VDR and cofactors in several cell lines, including cells derived from intestine, bone, and monocytes, and found that the vitamin D(3) derivatives act as cell type-selective VDR modulators. The data indicate that side chain modification is useful in the development of VDR antagonists and tissue-selective modulators. Further elucidation of the molecular mechanisms of action of selective VDR modulators will be essential for their clinical application.
authors.affiliation: Department of Biochemistry, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yoshimoto
authors.forename: Manabu
authors.initials: M
authors.lastname: Matsunawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Uno
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003067:Coenzymes / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D056913:Mediator Complex Subunit 1; D008958:Models, Molecular; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D015820:Cadherins; D003067:Coenzymes; D007783:Lactones; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D051958:Nuclear Receptor Coactivator 2; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002762:Cholecalciferol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D000218:Adamantane