The antagonism between 2-methyl-1,25-dihydroxyvitamin D3 and 2-methyl-20-epi-1,25-dihydroxyvitamin D3 in non-genomic pathway-mediated biological responses induced by 1α,25-dihydroxyvitamin D3 assessed by NB4 cell differentiation
| Autor: | Toshie Fujishima, Daishiro Miura, Anthony W. Norman, Atsushi Kittaka, Hiroaki Takayama, Seiichi Ishizuka, Mathew T. Mizwicki, Katsuhiro Konno |
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| Rok vydání: | 2005 |
| Předmět: |
Transcription
Genetic 1α 25 dihydroxyvitamin d3 Protein Conformation Stereochemistry Endocrinology Diabetes and Metabolism Cellular differentiation Clinical Biochemistry Alpha (ethology) Biochemistry Endocrinology Calcitriol Cytochrome P-450 Enzyme System Tumor Cells Cultured Humans Vitamin D Vitamin D3 24-Hydroxylase Receptor Molecular Biology Conformational isomerism Chemistry Diastereomer Cell Differentiation Cell Biology Ligand (biochemistry) Steroid Hydroxylases Receptors Calcitriol Molecular Medicine Antagonism |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 94:469-479 |
| ISSN: | 0960-0760 |
| DOI: | 10.1016/j.jsbmb.2005.01.025 |
| Popis: | We synthesized all eight possible A-ring diastereomers of 2-methyl substituted analogs of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] and also all eight A-ring diastereomers of 2-methyl-20-epi-1alpha,25(OH)2D3. Their biological activities, especially the antagonistic effect on non-genomic pathway-mediated responses induced by 1alpha,25(OH)2D3 or its 6-s-cis-conformer analog, 1alpha,25(OH)2-lumisterol3, were assessed using an NB4 cell differentiation system. Antagonistic activity was observed for the 1beta-hydroxyl diastereomers, including 2beta-methyl-1beta,25(OH)2D3 and 2beta-methyl-3-epi-1beta,25(OH)2D3. Very interestingly, 2beta-methyl-3-epi-1alpha,25(OH)2D3 also antagonized the non-genomic pathway, despite its 1alpha-hydroxyl group. Other 1alpha-hydroxyl diastereomers did not show antagonistic activity. 20-epimerization diminished the antagonistic effect of all of these analogs on the non-genomic pathway. These findings suggested that the combination of the 2-methyl substitution of the A-ring and 20-epimerization of the side chain could alter the biological activities in terms of antagonism of non-genomic pathway-mediated biological response. Based on a previous report, 2-methyl substitution alters the equilibrium of the A-ring conformation between the alpha- and beta-chair conformers. The 2beta-methyl diastereomers, which exhibited antagonism on non-genomic pathway-mediated response, were considered to prefer the beta-conformer. Further examination to elucidate the relationship between the altered ligand shape and receptors interaction will be important for molecular level understanding of the mechanism of antagonism of the non-genomic pathway. |
| Databáze: | OpenAIRE |
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