deficiency became a significant public health problem as a by-product of industrialization. Urban living, smog, and increased indoor activity limit exposure of the populace to sunshine and hence endogenous production of vitamin D3. This problem is readily addressed by adding vitamin D to foods, particularly milk.
1,25-Dihydroxy-vitamin D3 also fits the description of a hormone in the respect that it travels through the blood in small amounts from its site of production to affect cells at distant sites. Another major difference between a vitamin and a hormone is that vitamins usually are cofactors in metabolic reactions, whereas hormones behave as regulators and interact with specific receptors. 1,25(OH)2D3 produces many of its biological effects in a manner characteristic of steroid hormones (see Chapter 2). It binds to a specific nuclear receptor that is a member of the same superfamily as the receptors for steroid and thyroid hormones.
The form of vitamin D produced in mammals is called cholecalciferol, or vitamin D3; it differs from vitamin D2 (ergosterol), which is produced in plants, only in the length of the side chain. Irradiation of the skin results in photolysis of the bond that links carbons 9 and 10 in 7-dehydrocholesterol, and thus opens the B ring of the steroid nucleus (Fig. 15). The resultant cholecalciferol is biologically inert but, unlike its precursor, has a high affinity for a vitamin D-binding protein in plasma. Vitamin D3 is transported by the blood to the liver, where it is oxidized to form 25-hydroxycholecalciferol (25OH-D3) by the same P450 mitochondrial enzyme that oxidizes cholesterol on carbons 26 and 27 in the pathway leading to formation of bile acids. This reaction appears to be controlled only by the availability of substrate. 25OH-D3 has high affinity for the vitamin D-binding protein and is the major circulating form of vitamin D. It has little biological activity. In the proximal tubules of the kidney, a second hydroxyl group is added at carbon 1 by another P450 enzyme to yield the compound, 1,25(OH)2D3, which is about 1000 times as active as 25 OH-D3, and probably accounts for all of the biological activity of vitamin D. 1,25(OH)2D3 is considerably less abundant in blood than its 25 hydroxylated precursor and binds less tightly to vitamin D-binding globulin than its precursor 25 OH-D3. Consequently, 1,25(OH)2D3 has a half-life in blood of 15 hr compared to 15 days for 25 OH-D3.
Physiologic Actions of 1,25(OH)2D3
Overall, the principal physiologic actions of 1,25(OH)2D3 increase calcium and phosphate concentrations in extracellular fluid. These effects are exerted primarily on intestine and bone and, to a lesser extent, on kidney. Vitamin D receptors are widely distributed, however, and a variety of other actions that are not obviously related to calcium balance have been described or postulated. Because these latter effects are neither well understood nor germane to regulation of calcium balance, they are not discussed further.
Uptake of dietary calcium and phosphate depends on active transport by epithelial cells lining the small intestine. Deficiency of vitamin D severely impairs intestinal transport of both calcium and phosphorus. Although calcium uptake is usually accompanied by phosphate uptake, the two ions are transported by independent mechanisms, both of which are stimulated by 1,25(OH)2D3. Increased uptake of calcium is seen about 2 hr after 1,25(OH)2D3 is given to deficient subjects and is maximal within 4 hr. A much longer time is required when vitamin D is given, presumably because of the time needed for sequential hydroxylations in liver and kidney.
Calcium uptake by duodenal epithelial cells is illustrated in Fig. 16. Calcium enters passively down its electrochemical gradient through two novel channels, the epithelial calcium channel (ECaC) and calcium transporter 1 (CaT1). Upon entry into the cytosol calcium is bound virtually instantenously by calcium binding proteins called calbindins and carried through the cytosol to the basolateral membrane where it is extruded into the interstitium by calcium ATPase (calcium pump) and sodium/calcium cytosolic calcium concentration low and thus maintain a gradient favorable for calcium influx while affording protection from deleterious effects of high concentrations of free calcium. It appears the abundance of ECaC and CaTI in the luminal membrane and at least one of the calbindins in the cytosol depends on 1,25(OH)2D3 through regulation of gene transcription. Similarly, 1,25(OH)2D3 is thought to regulate expression of sodium phosphate transporters in the luminal membrane.
Some evidence obtained in experimental animals and in cultured cells suggests that 1,25,(OH)2D3 may also produce some rapid actions that are not mediated by altered genomic expression. Among these are rapid transport of calcium across the intestinal epithelium by a process that may involve both the IP3-DAG and the cyclic AMP second messenger systems (see Chapter 2) and the activation of membrane calcium channels. The physiologic importance of these rapid actions of 1,25,(OH)2D3 and the nature of the receptor that signals them are not known.
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