The Mode of Action of Vitamin D

Abstract

Summary 1. The purpose of this review article is to re‐evaluate and integrate many of the observations related to the physiological effects of vitamin D, using as a working hypothesis the concept that the vitamin may be acting analogously to a steroid hormone in terms of its ability to interact with genetic information and ultimately elicit a physiological response. Prior to this time the problem of the mechanism of action of vitamin D has primarily been approached from the point of view that the vitamin was acting as a cofactor for some specific enzymic reaction. 2. The physiological activities of vitamin D are integrated with those of parathyroid hormone to provide a homeostatic control for the regulation of primarily calcium and secondarily phosphate metabolism. It is proposed that the role of vitamin D in this homeostatic control mechanism is older and more fundamental than that of parathyroid hormone. The interaction of vitamin D on skeletal calcium metabolism may have evolved before the effects of the vitamin on intestinal calcium absorption. 3. There are several physiological defects of calcium metabolism—rickets, osteo‐malacia, vitamin D‐resistant rickets and idiopathic hypercalcaemia—all of which may be a consequence of an aberration in one or another of the interlocking steps of the vitamin D‐dependent and calcium‐dependent homeostatic control mechanism. 4. The most thoroughly established action of vitamin D in vivo is to promote or facilitate the intestinal absorption of calcium. Although the exact biochemical details of this process are not available, this may involve vitamin D‐mediated synthesis of the appropriate enzyme systems or the alteration of membrane structure necessary for calcium absorption. It is not yet unequivocally established whether calcium absorption is an energy‐dependent active transport process or is a passive carrier‐mediated or simple diffusion process. 5. The exact action of vitamin D on bone metabolism is not as well established, but the primary effect of the vitamin is likely to mediate bone resorption. The vitamin D‐dependent activities of the cell in both the intestine and bone are to absorb calcium and transfer it to the blood. 6. No direct effects of vitamin D on intestinal absorption of phosphate have been found. Furthermore the validity of a vitamin D‐mediated renal reabsorption of phosphate is questioned, for the major effects of vitamin D are cation oriented. If the renal effects of vitamin D are true, it is postulated that the mechanism of action of the vitamin here on the anion, phosphate, is fundamentally different from its cation oriented mechanism. 7. There is a lag in the action of vitamin D on the vitamin mediated: (a) transport of calcium both in vivo in rats and chicks, and in vitro with everted intestinal slices; (b) the apparent increased permeability of intestinal mucosa; (c) increased levels of citric acid in serum or bone; (d) the increased incorporation of radioactive inorganic phosphorus into intestinal mucosa phospholipids. As shown by the use of radi...

Radioligand receptor assay for 25-hydroxyvitamin D2/D3 and 1 alpha, 25-dihydroxyvitamin D2/D3.

“…Rats were chosen for the study because it is thought that these animals do not discriminate between cholecalciferol and ergocalciferol as does the chick (16). Two groups of animals were raised for 3 wk on a normal calcium (0.6%) and phosphorus (0.6%) diet.…”

25-hydroxycholecalciferol stimulation of muscle metabolism.

“…Although muscle wasting and weakness are prominent features of nutritional rickets (16)(17)(18)(19), a direct action of the vitamin on muscle metabolism and growth has heretofore not been appreciated. The generalized growth failure characteristic of vitamin D deficiency has previously been attributed to the failure of skeletal growth and the disordered calcium and phosphorus homeostasis attributed to the action of the vitamin on intestinal transport of these ions (4,5 The apparent specificity of the muscle response to 25-OHD3 and the failure of the muscle to respond to physiologic concentrations of 1,25-(OH) 2D3 is of obvious interest. This biologic specificity for 25-OHD3 is supported by the finding of a muscle cytosol protein fraction which specifically binds 25-OHD3.…”

“…The influence of vitamin D on intestinal transport of calcium and phosphorus and the influence of the vitamin on the maintenance of normal skeletal growth have been well established (1)(2)(3)(4)(5)(6)(8)(9)(10). Although muscle wasting and weakness are prominent features of nutritional rickets (16)(17)(18)(19), a direct action of the vitamin on muscle metabolism and growth has heretofore not been appreciated.…”

“…This increase in musculoskeletal growth has been attributed to the specific action of vitamin D on calcium homeostasis and specifically, the increase in intestinal absorption of calcium and secondarily an increase in bone mineralization and growth (4,5). More recently a direct action of vitamin D on bone has been recognized which is characterized by the stimulation of osteoclastic bone resorption (6).…”

Vitamin D Dependent Calcium Binding Protein in Rat Intestinal Mucosa

“…However, there was a lag in time between the administration of. vitamin D3 and the enhancement of calcium absorption (2). Recently during this lag time, it has been considered that vitamin D3 or its derivatives would act on the synthesis of carrier protein which facilitates calcium absorption in the in testinal mucosa (3).…”