| Autor: |
Peluso-Iltis C; Institute of Genetics and Molecular and Cellular Biology (IGBMC), 67400 Illkirch, France.; CNRS UMR 7104, 67400 Illkirch, France.; Inserm U1258, 67400 Illkirch, France.; University of Strasbourg, 67400 Illkirch, France., Pierrat N; Institute of Genetics and Molecular and Cellular Biology (IGBMC), 67400 Illkirch, France.; CNRS UMR 7104, 67400 Illkirch, France.; Inserm U1258, 67400 Illkirch, France.; University of Strasbourg, 67400 Illkirch, France., Rovito D; Institute of Genetics and Molecular and Cellular Biology (IGBMC), 67400 Illkirch, France.; CNRS UMR 7104, 67400 Illkirch, France.; Inserm U1258, 67400 Illkirch, France.; University of Strasbourg, 67400 Illkirch, France., Osz J; Institute of Genetics and Molecular and Cellular Biology (IGBMC), 67400 Illkirch, France.; CNRS UMR 7104, 67400 Illkirch, France.; Inserm U1258, 67400 Illkirch, France.; University of Strasbourg, 67400 Illkirch, France., Sawada D; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan., Kittaka A; Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan., Laverny G; Institute of Genetics and Molecular and Cellular Biology (IGBMC), 67400 Illkirch, France.; CNRS UMR 7104, 67400 Illkirch, France.; Inserm U1258, 67400 Illkirch, France.; University of Strasbourg, 67400 Illkirch, France., Rochel N; Institute of Genetics and Molecular and Cellular Biology (IGBMC), 67400 Illkirch, France.; CNRS UMR 7104, 67400 Illkirch, France.; Inserm U1258, 67400 Illkirch, France.; University of Strasbourg, 67400 Illkirch, France. |
| Abstrakt: |
The active vitamin D metabolites, 25-hydroxyvitamin D 3 (25D 3 ) and 1,25-dihydroxyvitamin D 3 (1,25D 3 ), are produced by successive hydroxylation steps and play key roles in several cellular processes. However, alternative metabolic pathways exist, and among them, the 4-hydroxylation of 25D 3 is a major one. This study aims to investigate the structure-activity relationships of 4-hydroxy derivatives of 1,25D 3 . Structural analysis indicates that 1,4α,25(OH) 3 D 3 and 1,4β,25(OH) 3 D 3 maintain the anchoring hydrogen bonds of 1,25D 3 and form additional interactions, stabilizing the active conformation of VDR. In addition, 1,4α,25D 3 and 1,4β,25D 3 are as potent as 1,25D 3 in regulating the expression of VDR target genes in rat intestinal epithelial cells and in the mouse kidney. Moreover, these two 4-hydroxy derivatives promote hypercalcemia in mice at a dose similar to that of the parent compound. |
