Mechanisms for the selective actions of vitamin D analogues.

The wide range of activities now attributed to 1,25(OH)2D3 has suggested numerous potential therapeutic applications for this vitamin D hormone, including inhibiting growth of various type of cancer. Unfortunately, the potent calcemic activity of the natural hormone has precluded its use in most cases. Vitamin D analogs with higher therapeutic indices offer renewed hope for treatment of malignancies. The promising analogs currently under study were selected from hundreds of candidates by in vitro screening followed by in vivo testing. The mechanism(s) responsible for the greater effectiveness of most of these compounds is not known. Our current understanding of vitamin D physiology and biochemistry suggests that the biological profile of an analog would be determined primarily by its interaction with four classes of proteins: 1) the nuclear vitamin D receptor (VDR) that mediates transcriptional regulation; 2) the metabolic enzymes, primarily the vitamin D-24-hydroxylase but possibly others; 3) serum transporters, mainly vitamin D binding protein (DBP), and perhaps lipoproteins; and 4) a new class of receptors that reside in the plasma membrane and mediate rapid, nongenomic responses. This article discusses how the manner in which analogs associate with these proteins can potentially produce selective actions at the tissue, cell and gene level. A thorough understanding of the influence of these analog/protein interactions on the biological profile of vitamin D analogs will be invaluable for the design of future analogs with enhanced target specificity.