of micelles in the intestinal lumen, vitamin D esters are hydrolyzed, and free vitamin D, usually as cholecalciferol or ergocalciferol, is absorbed by passive diffusion into the en-terocytes. There, it is incorporated into chylomicrons and secreted into the lymph where it enters the circulation.62 Cholecalciferol and ergocalciferol were once thought to be the active forms of vitamin D; however, they have now been identified as provitamins because they require hydroxyla-tion by the liver and the kidney to be fully active.

As shown in Figure 28.8, the first step occurs in the liver, following uptake from chylomicron remnants, by the enzyme vitamin D3 25-hydroxylase (EC 1.14.15.-). This enzyme converts the provitamin to calcidiol (previously 25-hydroxyvitamin D3, 25(OH)D3) and requires both molecular oxygen and reduced NADPH. The enzyme is found on the inner mitochondrial membrane,63 and the rate correlates with substrate concentration. Following secretion into the blood, calcidiol and other forms of vitamin D are associated with group-specific component (vitamin D-binding protein [GC]) formerly referred to as vitamin D-binding protein (VDBP). The calcidiol bound to GC is the major circulating form of the vitamin and may be stored in fats and muscle for prolonged periods. GC binding helps in the transport of vitamin Ds in blood and also prolongs the circulatory half-lives by making them less susceptible to hepatic metabolism and biliary excretion.64 Albumin and lipoproteins also bind vitamin Ds but with lower affinity than GC. The circulating levels of calcidiol are proportional to vitamin D intake and synthesis; thus, plasma levels of calcidiol have been used to indicate vitamin D status.65

The epithelial cells of the proximal convoluted tubules in the kidneys convert calcidiol to calcitriol [previously 1a,25-dihydroxyvitamin D3, 1a,25(OH)2D3] by the enzyme calcidiol 1-monooxygenase (EC also known previously as 25(OH)D3 1a-hydroxylase. The activity of this mitochondrial, cytochrome P450 enzyme is increased by parathyroid hormone and hypophosphatemia and decreased by calcitriol and Ca2+.66 Understanding this final step is crucial because renal disease can lead to deficiency of the active calcitriol and subsequent derangements in calcium and bone metabolism. Treatment is only effective if a vitamin D preparation that already has the 1a-hydroxy is used. Similar to cholecalciferol, ergocalciferol also requires hydroxylation in the liver and kidney to become fully active as shown in Figure 28.9.

In a classical sense, cholecalciferol, the form produced in animals, is not a true vitamin because it is produced in the

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