VITAMIN D: RECENT ADVANCES

Abstract

The field of vitamin D metabolism and mechanism of action has continued to be very active. Autoradiography has shown specific nuclear localization of 1,25-(OH)2D3 in target organs prior to initiation of mechanism of action. Specific nuclear localization has also been demonstrated in a variety of other tissues not previously appreciated as targets of vitamin D action, suggesting the possibility that vitamin D carries out subtle functions previously unappreciated. A macromolecule believed to be a receptor that specifically binds 1,35-(OH)2D3 has been found in the cells showing nuclear localization and in a number of tumor and cancer cell lines. Since 1,25-(OH)2D3 has been found to cause differentiation of certain myeloid leukemia cells, a possible relationship between the vitamin D system and cancer has appeared. Substantial evidence exists that 1,25-(OH)2D3 functions in a nuclear-mediated process, although some evidence exists that not all of the actions of 1,25-(OH)2D3 are carried out through such a mechanism. Substantial advances in our understanding of the metabolism of vitamin D have also been made. The presence of significant amounts of 1 alpha-hydroxylase has been located in the placenta in addition to the kidney. Although there have been reports of extrarenal synthesis of 1,25-(OH)2D3, these sites, if they produce 1,25-(OH)2D3, produce it in insufficient amounts for function. The renal 1 alpha-hydroxylase has been solubilized and shown to be a three-component system. The 25-hydroxylase in the liver has also been solubilized and shown to be a two-component mixed-function monooxygenase. New pathways of vitamin D metabolism include a 23-oxidation to form 23,25-(OH)2D3 or a 23-hydroxylated form of 1,25-(OH)2D3. 23,25-(OH)2D3 is further oxidized to produce a 25-(OH)2D3-26,23-lactone. Although these pathways are of significant magnitude, their roles remain unknown since the products have low biological activity. Important analogs of the vitamin D metabolites include 24,24-F2-25-OH-D3 and the 26,26,26,27,27,27-F6-25-OH-D3. These have been used to show that the 24-hydroxylation, the 26-hydroxylation, and the lactone formation do not play a significant role in the function of vitamin D. Their 1-hydroxy analogs have also been prepared and shown to be extremely biologically active, being somewhere around ten times more active than the native 1,25-dihydroxyvitamin D3, illustrating that important analogs of the vitamin D system continue to be discovered.