Vitamin D
Vitamin D is absorbed in the presence of bile, probably from the jejunum and is transported like vitamin A in the lymph chylomicrons to the bloodstream. It is rapidly taken up by the liver, where it is hydroxylated to 25hydroxycholecalciferol (25-0H-D3). D3 formed in the sl:in or injected as an alcohol solution also is removed by the liver.31 Released from the liver, 25-0H-D3 undergoes another hydroxylation in the kidney to form 1-25-(OH)2D3' which is the active hormone in the vitamin D endocrine system. 32 A number of other metabolites have been identified in the kidney, liver, and intestine, but, although they may show some vitamin D activity, their functional significance is unknown. Of these, .24,25-(OH)2D3' formed from 25-0H-D3 in the kidney and the intestine, has received most attention because it is found in relatively large amounts in the plasma, and its production appears to be governed by the regulatory system that controls the production of 1,25-( OH) 2D3. Recent research provides strong evidence against a specific requirement for .24-hydroxylation for activity in bone mineralization as has been proposed.
Vitamin D3 and its metabolites are transported in the plasma bound to an a-globulin that has not been well characterized. The major circulating form of vitamin D is 25-0H-D3.
Although administration of vitamin D results in an initial uptake by the liver and in increased formation of 25-0H-D3, the excess vitamin appears to be stored mostly in the adipose tissue. Considerable amounts are also found in the liver and other tissuesY The major route of vitamin D excretion is through the bile; some metabolites are found also in the urine, but as is the case with vitamin A, daily loss of vitamin D by urinary excretion is small.
Functions
Current research on the action of vitamin D is rapidly olding its relationship to calcium and phosphorus metabolism. The major function of vitamin D presently own is to elevate the concentration of plasma calcium d phosphorus to levels that allow normal bone mineralnon and prevent the tetany of hypocalcemia. To accomplish this, vitamin D acts at a number of erent sites.
Absorption of calcium and phosphorus from the estinal tract
Elevation of plasma calcium from dietary intake involves vitamin D-stimulated active transport of calcium from the intestinal lumen to the bloodstream against a concentration gradient. This process takes place throughout the intestine including the colon, but is most active in duodenum. The function of 1,25-(OH)2D3 in the enhnncement of calcium transport includes multiple actions, which are not well understood. Carried by blood to the intestine, 1,25-(OH)2D3 binds to a cytosomal receptor of the mucosal cell and is translocated to the nucleus, where its interaction with the genome is presumed to initiate protein synthesis that includes a specific calciumbinding protein (CaBP). Although 1,25-(OH)2D3 stimulates both the entry of calcium into the epithelial cell at the brushborder and its exit to the serosa through the basolateral membrane of the cell, only the latter process requires new protein synthesis. Stimulation of calcium uptake by 1,25-(OH)2D3 at the brushborder is rapid and precedes the vitamin D-induced production of CaBP, which is followed by enhancement of calcium exit from the cell. The function of CaBP remains uncertain, but it may entail transfer of calcium from its intracellular transport vehicles (mitochondria or membrane vesicles) to the basolateral cation pump for extrusion from the cell. Although the mechanism of this calcium release is not certain, experimental evidence supports an ATPasedependent exit of calcium in exchange for entering sodium.
Other observations after administration of 1,25-(OH)2D3 include stimulation of adenyl cyclase (and an increase in cAMP) and an increase in alkaline phosphatase. No direct role for alkaline phosphatase in the absorption of calcium is indicated, and it has been suggested that perhaps it hydrolyzes organic complexes of calcium and phosphorus at the brushborder, thereby increasing their availability for absorption. The role of cAMP is also uncertain, but some evidence suggests that it may in someway aid the entry of calcium into the mucosal cell and may, perhaps, act as a mediator of the trophic action of 1,25-(OH)2D3 on the intestine; this "second messenger" role of cAMP is well known in the action of several other hormones.
It should be noted that some calcium absorption takes place by mechanisms independent of vitamin D. The amount of calcium absorbed without vitamin D under most circumstances is not adequate to satisfY the calcium requirement, as is evident from the development of rickets in children and osteomalacia in adults. It has been long recognized that the rate of intestinal absorption of calcium is responsive to the body's need for calcium and adapts to the level of calcium intake. This adaptation is dependent on the availability of1,25-(OH)2D3 and is mediated by the parathyroid hormone (PTH).30 However, it appears that under conditions of high calcium need, such as pregnancy and lactation, other adaptive mechanisms may also be functioning.
Intestinal absorption of phosphorus also involves at least two mechanisms, both of which are stimulated by vitamin D.32 Because the vitamin D-dependent active absorption of calcium results in increased absorption of phosphorus as an accompanying anion, the effect on phosphorus absorption is secondary. Phosphorus is also transported by an active transport process that is stimulated by vitamin D, requires sodium, but does not result in transport of calcium.
Mobilization of calcium and phosphorus from the bone
The normal level of plasma calcium and phosphorus is maintained within relatively narrow limits of concentration. When intestinal absorption is not taking place, bone serves as a reserve for calcium and phosphorus. The primary factor in the mobilization of these minerals from the bone fluid compartment is PTH, but the presence of 1,25-(OH)2D3 appears to be required for the process. It should be noted that while this mechanism is essential in the maintenance of calcium and phosphorus homeostasis, it cannot be drawn upon continuously without replacement by dietary intake.
Renal reabsorption of calcium and phosphorus
The third site for the control of plasma calcium and phosphorus levels is the kidney. When the plasma levels of these minerals are low the kidneys can increase their reabsorption, thereby reducing loss of them from the body. Vitamin D has been shown to stimulate the reabsorption of calcium in the distal tubules, but its role in phosphorus reabsorption is still controversial; the latest evidence does not support a vitamin D function in renal reabsorption of phosphorus.
Other functions
I t has long been suspected that vitamin D is required in the actual process of bone mineralization in addition to its function in providing supersaturation levels of calcium and phosphorus. Despite many attempts, direct proof for such function is still lacking. Vitamin D (1,25-(OH)2D3) appears to increase muscle strength in rachitic children and in patients with renal osteodystrophy. There is no information at present about how this effect might be brought about. Although uptake of radioactive 1,25-(OH)2D3 by tissues other than the previously known target tissues has been demonstrated recently, muscle was not among them.32 A search for possible new functions of vitamin D has led to a recent demonstration that 1,25-(OH)2D3 enhances the accumulation of 7-dehydrocholesterol in the skin in the rat, thereby increasing the substrate for the production of its prohormone, vitamin D3.
