title: Singly dehydroxylated A-ring analogues of 19-nor-1alpha,25-dihydroxyvitamin D3 and 19-nor-22-oxa-1alpha,25-dihydroxyvitamin D3: novel vitamin D3 analogues with potent transcriptional activity but extremely low affinity for vitamin D receptor.
abstract: 1Alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] mediates its biological activities through specific binding to the nuclear vitamin D receptor (VDR). The VDR, bound to 1alpha,25(OH)2D3, forms a heterodimer with a nuclear accessory factor, retinoid X receptor (RXR), and the complex subsequently binds to specific nucleotide sequences or a vitamin D-responsive element (VDRE) to induce gene transcriptions. Thus, an ideal analogue of 1alpha,25(OH)2D3 for therapeutic applications has been considered to be one which has a high binding affinity for VDR, thus forming a stable VDR/RXR complex, and binding strongly to VDRE. By contrast, we report here evidence contrary to this hypothesis. Several singly dehydroxylated A-ring analogues of 19-nor-1alpha,25-dihydroxyvitamin D3 and 19-nor-22-oxa-1alpha,25-dihydroxyvitamin D3, all of which have an extremely low binding affinity for VDR, and some of which lack the 1alpha-hydroxyl group that is considered to be essential for VDR-mediated gene expression, have greater or equivalent potencies to 1alpha,25(OH)2D3 for inhibiting the proliferation and inducing the differentiation of HL-60 cells, as well as inducing the transactivation of a luciferase reporter gene combining a rat 25-hydroxyvitamin D3 24-hydroxylase gene promoter containing two VDREs. The present findings open interesting possibilities as to the role of the VDR in the genomic action of 1alpha,25(OH)2D3 and the development of new 19-nor-analogues of 1alpha,25(OH)2D3.
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Okano
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: N
authors.initials: N
authors.lastname: Tsugawa
authors.forename: K
authors.initials: K
authors.lastname: Ozono
authors.forename: N
authors.initials: N
authors.lastname: Kubodera
authors.forename: A
authors.initials: A
authors.lastname: Osawa
authors.forename: M
authors.initials: M
authors.lastname: Terada
authors.forename: K
authors.initials: K
authors.lastname: Mikami
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014809:Vitamin D-Binding Protein / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; D002762:Cholecalciferol; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase