Regulation of Vitamin D Metabolism

The main physiologictd function of vittunin D is in the control of calcium homeostasis, and vittunin D metabolism is regulated largely by the state of 

1 Calcitriol The major determinant ofthe relative activities of calcidiol 1 -hydroxylase and 24-hydroxylase is the avaUahUity of calcitriol. In vitamin D-deficient animals, with low circulating concentrations of calcitriol, the activity of 1 -hydroxylase in the kidneys is maximal. There is litde or no detectable 24-hydroxylase activity. Both in vivo and in isolated kidney cells in culture, the addition of calcitriol results in induction of the 24-hydroxylase and repression of 1 -hydroxylase removal of calcitriol from the culture medium results in induction of 1-hydroxylase and repression of 24-hydroxylase. 

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Cholecalciferol 25-hydroxylase is not restricted to the liver kidneys, skin, and gut microsomes also have a cytochrome P450 -dependent enzyme that catalyzes the 25-hydroxylation of cholecalciferol and la-hydroxycholecalciferol, hut not ergocalciferol. Although there is some evidence that calcitriol can reduce the activity of calciferol 25-hydroxylase, it is not known whether this is physiologically important the major factor controlling 25-hydroxylation is the rate of uptake of cholecalciferol into the liver. It is the fate of calcidiol in the kidneys that provides the most important regulation of vitamin D metabolism (Wikvall, 2001). 

Reddy GS, Norman AW, Willis DM, Goltzman D, Guyda H, Solomon S, et al. Regulation of vitamin D metabolism in normal human pregnancy. J Clin Endocrinol Metab 1983 56 363-70. 

Bland, R., E.A. Walker, S.V. Hughes, P.M. Stewart, and M. Hewison (1999). Constitutive expression of 25-hydroxyvitamin Dj-la-hydroxylase in a transformed human proximal tubule cell line Evidence for direct regulation of vitamin D metabolism by calcium. Endocrinology 140, 2027-2034. 

Regulation of Vitamin D Metabolism - It is well established that hypocalcemia markedly stimulates la-hydroxylatlon of 25-OH-D to form... 

Vitamin D functions in the process of calcium mobilization from previously formed bone making it available to the extracellular fluid upon demand by the calcium homeostatic system as described under the regulation of vitamin D metabolism. From the experiments described in the metabolism section it is clear that 1, 25-(0H)2D3, rather than 25-OH-D3 or vitamin D3 functions in the mobilization of calcium from bone under physiologic conditions. The mechanism whereby 1,25-(0H)2D3 initiates mobilization of calcium from bone is not at all understood. In contrast to the response of intestinal calcium transport to 1, 25-(0H)2D3 this process is blocked by the prior administration of actinomycin D suggesting that in fact a transcriptive event is involved in this activation As previously pointed out, bone possesses a specific receptor for 1,25bone cells has not yet been determined however. In vivo the 1,25-(OH)2D3 activation of bone calcium mobilization requires the presence of parathyroid hormone but the nature of... 

Stamp et al, (48 ) suggested that plasma calcium concentrations among epileptics may be regulated by effects of anticonvulsants on mechanisms other than those concerning vitamin D, i.e. that it is not related to hepatic induction of vitamin D-metabolizing enzymes as has been thought. 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

T FIGURE 10-20 Vitamin D3 production and metabolism, (a) Cholecalciferol (vitamin D3) is produced in the skin by UV irradiation of 7-dehydrocholesterol, which breaks the bond shaded pink. In the liver, a hydroxyl group is added at C-25 (pink) in the kidney, a second hydroxylation at C-1 (pink) produces the active hormone, 1,25-dihydroxycholecalciferol. This hormone regulates the metabolism of Ca2+ in kidney, intestine, and bone, (b) Dietary vitamin D prevents rickets, a disease once common in cold climates where heavy clothing blocks the UV component of sunlight necessary for the production of vitamin D3 in skin. On the left is a 21/2-year-old boy with severe rickets on the right, the same boy at age 5, after 14 months of vitamin D therapy. 

FIGURE 29.5 Chemical structure of vitamin D (calciferol, term for a collection of fat-soluble steroid-like substances that are regulating the calcium and phosphate metabolism). Cholecalciferol (R =R2=R3=H), Calcitriol (R1=R2=OH, R3=H). 

Vitamin D that is taken up by the fiver is converted to 25-hydroxyvitamin D by a microsomal hydroxylase (Fig. 30-3). 25-Hydroxyvitamin D is the main circulating form of vitamin D in the serum and the best indicator of vitamin D status. Normal serum levels are 14-60 ng/mL (35-150 nmol/L). When serum calcium concentrations decline, 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitmin D by la-hydroxylase, a mixed-function oxidase that is located in the inner mitochondrial membrane in kidney tissue and whose expression is regulated by parathyroid hormone (PTH). The main function of 1,25-dihydroxyvitamin D is to increase the intestinal absorption of dietary calcium and phosphorus. When serum concentrations of calcium and phosphorus are normal or when large doses of vitamin D are administered, 25-hydroxyvitamin D is metabolized to 24,25-dihydroxyvitamin D in the renal... 

It is now well established that l,25-(OH)2D3 is the active hormonal form of vitamin D3 [32], The production of l,25-(OH)2D3 in the kidney is regulated by dietary calcium and phosphate and also by changes in serum calcium and parathyroid hormone, which clearly highlight the hormonal nature of this compound. Functionally, the three classical actions of l,25-(OH)2D3 are to stimulate intestinal calcium and independently phosphate absorption, the mobilization of calcium from bone, and increase renal reabsorption of calcium. The focus of this review will be to explore the most recent concepts of vitamin D in regard to its metabolism and physiology, and with respect to the medicinal applications of vitamin D3 metabolites and analogues. 

Parathyroid Hormone Parathyroid hormone raises plasma calcium by direct effects on bone resorption and renal reabsorption of calcium, and indirectly by regulating the metabolism of vitamin D. It is a peptide and acts via cell surface G-protein receptors linked to adenylate cyclase. The parathyroid glands have G-protein cell surface calcium receptors linked to phospholipase G, and parathyroid hormone is secreted in response to hypocalcemia. Magnesium is required for secretion of the hormone, which may explain the development of hypocalcemia in premature infants who are magnesium deficient. 

Biochemistry of Vtamin D Assessment of Vtamin D Status Action of 1 -Dihydroxyvitamin 03 in Regulating Transcriptkm Vitamin D Deficiency Phosphate Metabolism Treatment of Vitamin D Ddidency and Hazards of High Intake... 

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