FIGURE 42–3 Conversion of 7-dehydrocholesterol to vitamin D3 in the skin and its subsequent metabolism to 25-hydroxyvitamin D3 (25[OH]D3) in the liver and to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) and 24,25-dihydroxyvitamin D3 (24,25[OH]2D3) in the kidney. Control of vitamin D metabolism is exerted primarily at the level of the kidney, where high concentrations of serum phosphorus (P) and calcium (Ca) as well as fibroblast growth factor 23 (FGF23) inhibit production of 1,25(OH)2D3 (indicated by a minus [−] sign), but promote that of 24,25(OH)2D3 (indicated by a plus [+] sign). Parathyroid hormone (PTH), on the other hand, stimulates 1,25(OH)2D3 production but inhibits 24,25(OH)2D3 production. The insert (shaded) shows the side chain for ergosterol, vitamin D2, and the active vitamin D2 metabolites. Ergosterol is converted to vitamin D2 (ergocalciferol) by UV radiation similar to the conversion of 7-dehydrocholesterol to vitamin D3. Vitamin D2, in turn, is metabolized to 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D2 via the same enzymes that metabolize vitamin D3. In humans, corresponding D2 and D3 metabolites have equivalent biologic effects, although they differ in pharmacokinetics. +, facilitation; –, inhibition; P, phosphorus; Ca, calcium; PTH, parathyroid hormone; FGF23, fibroblast growth factor 23.
of DBP in the population with different affinities for the vitamin D metabolites, and, as noted earlier, the affinity of DBP for the D2 metabolites is less than that for the D3 metabolites. Thus individuals can vary with respect to the fraction of free metabolite available, so that measuring only the total metabolite concentration may be misleading with respect to assessing vitamin D status. In normal subjects, the terminal half-life of injected calcifediol (25[OH]D) is around 23 days, whereas in anephric subjects it is around 42 days. The half-life of 24,25(OH)2D is probably similar. Tracer studies with vitamin D have shown a rapid clearance from the blood. The liver appears to be the principal organ for clearance. Excess vitamin D is stored in adipose tissue. The metabolic clearance of calcitriol (1,25[OH]2D) in humans likewise indicates a rapid turnover, with a terminal half-life measured in hours. Several of the 1,25(OH)2D analogs are bound poorly by DBP. As a result, their clearance is very rapid, with a terminal half-life of minutes. Such analogs have less hypercalcemic, hypercalciuric effects than calcitriol, an important aspect of their use in the management of conditions such as psoriasis and hyperparathyroidism.
The mechanism of action of the vitamin D metabolites remains under active investigation. However, 1,25(OH)2D is well established as the most potent stimulant of intestinal calcium and phosphate transport and bone resorption. 1,25(OH)2D appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the
TABLE 42–1 Vitamin D and its major metabolites and analogs.