(23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone function as antagonists of vitamin D receptor-mediated genomic actions of 1alpha,25-dihydroxyvitamin D(3).
We synthesized various analogues of 1alpha,25-(OH)(2)D(3)-26,23-lactone and examined the effects of them on HL-60 cell differentiation using the evaluation system of the genomic action of 1alpha,25-(OH)(2)D(3). We found that (23S)- and (23R)-25-dehydro-1alpha-OH-D(3)-26,23-lactone (TEI-9647 and TEI-9648) strongly bound to the VDR, but did not induce HL-60 cell differentiation. Intriguingly, TEI-9647 and TEI-9648 did inhibit that induced by 1alpha,25-(OH)(2)D(3), whereas they did not suppress that caused by retinoic acid or TPA. On the contrary, the similar 25-dehydrated 24-dehydro analogues, TEI-D1807 and TEI-D1808, weakly but significantly induced HL-60 cell differentiation, never showing inhibitory effect on HL-60 cell differentiation induced by 1alpha,25-(OH)(2)D(3). In other experiments, TEI-9647 and TEI-9648 markedly suppressed 25-OH-D(3)-24-hydroxylase gene expression induced by 1alpha,25-(OH)(2)D(3) in HL-60 cells. TEI-9647 also inhibited the heterodimer formation between VDR and RXRalpha, and the VDR interaction with co-activator SRC-1 according to the results obtained from the mammalian two-hybrid system in Saos-2 cells. Taking all these results into consideration, we reached a manifest conclusion that TEI-9647 and TEI-9648 are the specific and first antagonists of 1alpha,25-(OH)(2)D(3) action, specifically VDR-VDRE mediated genomic action.
Ishizuka
S
S
Department of Bone and Calcium Metabolism, Teijin Institute for Bio-Medical Research, 4-3-2 Asahigaoka, Hino, 191-8512, Tokyo, Japan. s.ishizuka@teijin.co.jp
Miura
D
D
Ozono
K
K
Saito
M
M
Eguchi
H
H
Chokki
M
M
Norman
A W
AW
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System; D019281:Dimerization; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D018922:HL-60 Cells / Q000166:cytology; D051548:Histone Acetyltransferases; D006801:Humans; D056920:Nuclear Receptor Coactivator 1; D011485:Protein Binding; D012333:RNA, Messenger / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D013237:Stereoisomerism; D013250:Steroid Hydroxylases / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C400545:TEI 9647; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D002117:Calcitriol