Abstract
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.