PDF(Pubmed)
Abstract：
The active vitamin D metabolites, 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), 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 25D3 is a major one. This study aims to investigate the structure-activity relationships of 4-hydroxy derivatives of 1,25D3. Structural analysis indicates that 1,4α,25(OH)3D3 and 1,4β,25(OH)3D3 maintain the anchoring hydrogen bonds of 1,25D3 and form additional interactions, stabilizing the active conformation of VDR. In addition, 1,4α,25D3 and 1,4β,25D3 are as potent as 1,25D3 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.
摘要：
活性维生素D代谢产物，25-羟基维生素D3（25D3）和1,25-二羟基维生素D3（1,25D3），是通过连续的羟基化步骤产生的，在几个细胞过程中起着关键作用。然而,存在替代代谢途径，其中,25D3的4-羟基化是主要的。本研究旨在研究1,25D3的4-羟基衍生物的构效关系。结构分析表明，1,4α，25（OH）3D3和1,4β，25（OH）3D3保持1,25D3的锚定氢键并形成额外的相互作用，稳定VDR的活性构象。此外,1,4α,25D3和1,4β，25D3在调节大鼠肠上皮细胞和小鼠肾脏中VDR靶基因的表达方面与1,25D3一样有效。此外，这两种4-羟基衍生物以与母体化合物相似的剂量促进小鼠高钙血症。
