Vitamin D: Production, Metabolism, and Mechanism of Action

Excerpt

Vitamin D production in the skin under the influence of sunlight (UVB) is maximized at levels of sunlight exposure that do not burn the skin. Further metabolism of vitamin D to its major circulating form (25(OH)D) and hormonal form (1,25(OH)2D) takes place in the liver and kidney, respectively, but also in other tissues where the 1,25(OH)2D produced serves a paracrine/autocrine function: examples include the skin, cells of the immune system, parathyroid gland, intestinal epithelium, prostate, and breast. Parathyroid hormone, FGF 23, calcium and phosphate are the major regulators of the renal 1-hydroxylase (CYP27B1, the enzyme producing 1,25(OH)2D); regulation of the extra renal 1-hydroxylase differs from that in the kidney and involves cytokines. The major enzyme that catabolizes 25(OH)D and 1,25(OH)2D is the 24-hydroxylase; like the 1-hydroxylase it is tightly controlled in the kidney in a manner opposite to that of the 1-hydroxylase, but like the 1-hydroxylase it is widespread in other tissues where its regulation is different from that of the kidney. Vitamin D and its metabolites are carried in the blood bound to vitamin D binding protein (DBP) and albumin—for most tissues it is the free (i.e.. unbound) metabolite that enters the cell; however, DBP bound metabolites can enter some cells such as the kidney and parathyroid gland through a megalin/cubilin mechanism. Most but not all actions of 1,25(OH)2D are mediated by the vitamin D receptor (VDR). VDR is a transcription factor that partners with other transcription factors such as retinoid X receptor that when bound to 1,25(OH)2D regulates gene transcription either positively or negatively depending on other cofactors to which it binds or interacts. The VDR is found in most cells, not just those involved with bone and mineral homeostasis (i.e.. bone, gut, kidney) resulting in widespread actions of 1,25(OH)2D on many physiological and pathologic processes. Animal studies indicate that vitamin D has beneficial effects on various cancers, blood pressure, heart disease, immunologic disorders, but these non-skeletal effects have been difficult to prove in humans in randomized controlled trials. Analogs of 1,25(OH)2D are being developed to achieve specificity for non-skeletal target tissues such as the parathyroid gland, skin, and cancers to avoid the hypercalcemia resulting from 1,25(OH)2D itself. The level of vitamin D intake and achieved serum levels of 25(OH)D that are optimal and safe for skeletal health and the non-skeletal actions remain controversial but are likely between an intake of 800-2000IU vitamin D in the diet and 20-50ng/ml 25(OH)D in the blood. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.