MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Toell, A.
Right arrow Articles by Carlberg, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Toell, A.
Right arrow Articles by Carlberg, C.

Vol. 59, Issue 6, 1478-1485, June 2001

Different Molecular Mechanisms of Vitamin D3 Receptor Antagonists

Andrea Toell, Manuel Macias Gonzalez, Dagmar Ruf, Andreas Steinmeyer, Seiichi Ishizuka, and Carsten Carlberg

Institut für Physiologische Chemie I and Biomedizinisches Forschungszentrum, Heinrich-Heine-Universität, Düsseldorf, Germany (A.T., M.M.G., D.R., C.C); Department of Biochemistry, University of Kuopio, Kuopio, Finland (M.M.G., C.C.); Medicinal Chemistry, Schering AG, Berlin, Germany (A.S.); and Department of Bone and Calcium Metabolism, Teijin Institute for Bio-Medical Research, Tokyo, Japan (S.I.)

Two structurally different antagonists of the nuclear hormone 1alpha ,25-dihydroxyvitamin D3 [1alpha ,25(OH)2D3], 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 1alpha ,25(OH)2D3 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 1alpha ,25(OH)2D3 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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
D. E. Prosser, M. Kaufmann, B. O'Leary, V. Byford, and G. Jones
Single A326G mutation converts human CYP24A1 from 25-OH-D3-24-hydroxylase into -23-hydroxylase, generating 1{alpha},25-(OH)2D3-26,23-lactone
PNAS, July 31, 2007; 104(31): 12673 - 12678.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. Lempiainen, F. Molnar, M. Macias Gonzalez, M. Perakyla, and C. Carlberg
Antagonist- and Inverse Agonist-Driven Interactions of the Vitamin D Receptor and the Constitutive Androstane Receptor with Corepressor Protein
Mol. Endocrinol., September 1, 2005; 19(9): 2258 - 2272.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
E. Ochiai, D. Miura, H. Eguchi, S. Ohara, K. Takenouchi, Y. Azuma, T. Kamimura, A. W. Norman, and S. Ishizuka
Molecular Mechanism of the Vitamin D Antagonistic Actions of (23S)-25-Dehydro-1{alpha}-Hydroxyvitamin D3-26,23-Lactone Depends on the Primary Structure of the Carboxyl-Terminal Region of the Vitamin D Receptor
Mol. Endocrinol., May 1, 2005; 19(5): 1147 - 1157.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
G. Eelen, L. Verlinden, N. Rochel, F. Claessens, P. De Clercq, M. Vandewalle, G. Tocchini-Valentini, D. Moras, R. Bouillon, and A. Verstuyf
Superagonistic Action of 14-epi-Analogs of 1,25-Dihydroxyvitamin D Explained by Vitamin D Receptor-Coactivator Interaction
Mol. Pharmacol., May 1, 2005; 67(5): 1566 - 1573.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. Ismail, C. V. Nguyen, A. Ahene, J. C. Fleet, M. R. Uskokovic, and S. Peleg
Effect of Cellular Environment on the Selective Activation of the Vitamin D Receptor by 1{alpha},25-Dihydroxyvitamin D3 and Its Analog 1{alpha}-Fluoro-16-Ene-20-Epi-23-Ene-26,27-Bishomo-25-Hydroxyvitamin D3 (Ro-26-9228)
Mol. Endocrinol., April 1, 2004; 18(4): 874 - 887.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. M. Gonzalez, P. Samenfeld, M. Perakyla, and C. Carlberg
Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor
Mol. Endocrinol., October 1, 2003; 17(10): 2028 - 2038.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics