Different Molecular Mechanisms of Vitamin D3 Receptor Antagonists
Two structurally different antagonists of the nuclear hormone 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ], the 25-carboxylic ester ZK159222 and the 26,23-lactone TEI-9647, have recently been described. In this study, the molecular mechanisms and the efficacy of both antagonists were compared. ZK...
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Published in | Molecular pharmacology Vol. 59; no. 6; p. 1478 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.06.2001
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Online Access | Get full text |
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Summary: | Two structurally different antagonists of the nuclear hormone 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ], the 25-carboxylic ester ZK159222 and the 26,23-lactone TEI-9647, have recently been described. In this study, the molecular
mechanisms and the efficacy of both antagonists were compared. ZK159222 showed similar potency and sensitivity to 1α,25(OH) 2 D 3 in ligand-dependent gel shift assays using the vitamin D receptor (VDR), the retinoid X receptor, and specific DNA binding
sites, whereas TEI-9647 displayed reduced potency and >10-fold lower sensitivity in this assay system. Limited protease digestion
and gel shift clipping assays showed that the two antagonists stabilized individual patterns of VDR conformations. Both antagonists
prevented the interaction of the VDR with coactivator proteins, as demonstrated by GST-pull-down and supershift assays; like
the natural hormone, however, they were able to induce a dissociation of corepressor proteins. Interestingly, ZK159222 demonstrated
functional antagonism in reporter gene assays both in HeLa and MCF-7 cells, whereas TEI-9647 functioned as a less sensitive
antagonist only in MCF-7 cells. In conclusion, the two 1α,25(OH) 2 D 3 analogs act in part via different molecular mechanisms, which allows us to speculate that ZK159222 is a more complete antagonist
and TEI-9647 a more selective antagonist. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.59.6.1478 |