Although vitamin D has numerous actions, its two dominant actions appear to be to enhance the availability of calcium and phosphate for new bone formation and to prevent an abnormal rise or fall in plasma calcium and phosphate levels such as symptomatic hypocalcemia and hypophosphatemia.
It does this by acting on all three primary sites of regulation of calcium balance.
First, vitamin D increases the production of several intestinal proteins, including a luminal membrane calcium channel and a high-affinity cytosolic calcium-binding protein (calbindin), that enhance transcellular absorption of calcium.
Second, in the kidney, vitamin D appears to act in a synergistic fashion with PTH to induce active calcium reabsorption in the distal convoluted tubule and connecting tubule by increasing the synthesis of a distinct luminal membrane calcium channel and a cytosolic calcium-binding protein (calbindin).
Third, vitamin D induces resorption of bone, mobilization of calcium, and bone mineralization after an elevation of plasma calcium levels.
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Structure and Synthesis
The term vitamin D refers to one or more members of a group of steroid molecules.
Vitamin D3, also known as cholecalciferol is generated in the skin of animals when light energy is absorbed by a precursor molecule 7-dehydrocholesterol. Vitamin D is thus not a true vitamin, because individuals with adequate exposure to sunlight do not require dietary supplementation. There are also dietary sources of vitamin D, including egg yolk, fish oil and a number of plants. The plant form of vitamin D is called vitamin D2 or ergosterol. However, natural diets typically do not contain adequate quantities of vitamin D, and exposure to sunlight or consumption of foodstuffs purposefully supplemented with vitamin D are necessary to prevent deficiencies.
Vitamin D, as either D3 or D2, does not have significant biological activity. Rather, it must be metabolized within the body to the hormonally-active form known as 1,25-dihydroxycholecalciferol. This transformation occurs in two steps, as depicted in the diagram to the right:
- Within the liver, cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by the enzyme 25-hydroxylase.
- Within the kidney, 25-hydroxycholecalciferol serves as a substrate for 1-alpha-hydroxylase, yielding 1,25-dihydroxycholecalciferol, the biologically active form.
Each of the forms of vitamin D is hydrophobic, and is transported in blood bound to carrier proteins. The major carrier is called, appropriately, vitamin D-binding protein. The halflife of 25-hydroxycholecalciferol is several weeks, while that of 1,25-dihydroxycholecalciferol is only a few hours.
Vitamin D is involved in the regulation of plasma calcium levels.
Its role in calcium metabolism first was recognized in the childhood disease rickets, which is associated with a deficiency of a fat-soluble vitamin and is characterized by a hypocalcemia with various skeletal abnormalities.
Vitamin D is present in the diet and can be synthesized in the skin from 7-dehydrocholesterol in the presence of ultraviolet light.
As Vitamin D passes through the liver, it is hydroxylated to 25-hydroxyvitamin D (25-hydroxycholecalciferol), the inactive form of vitamin D.
25-Hydroxyvitamin D travels by the circulation to the kidney, where proximal tubule cells contain the enzyme 1 α-hydroxylase, which converts the molecule to 1,25-dihydroxyvitamin D, the most active form of vitamin D.
The activity of the 1 α-hydroxylase is tightly controlled by PTH and plasma phosphate levels. PTH and hypophosphatemia stimulate 1 α-hydroxylase activity, resulting in elevated vitamin D levels and the maintenance of calcium (and phosphate) balance.
In contrast, low PTH levels and hyperphosphatemia inhibit the enzyme, reducing the production of vitamin D.