Calcitriol metabolism

Unlike the other fat-soluble vitamins, there is litde or no storage of vitamin D in the liver, except in oily fish. In human liver, concentrations of vitamin D do not exceed about 25 nmol per kg. Significant amounts may be present in adipose tissue, but this is not really storage of the vitamin, because it is released into the circulation as adipose tissue is catabolized, rather than in response to demand for the vitamin. The main storage of the vitamin seems to be as plasma calcidiol, which has a half-life of the order of 3 weeks (Holick, 1990). In temperate climates, there is a considerable seasonal variation, with plasma concentrations at the end of winter as low as half those seen at the end of summer (see Table 3.2). The major route of vitamin D excretion is in the bile, with less than 5% as a variety of water-soluble conjugates in urine. Calcitroic acid (see Figure 3.3) is the major product of calcitriol metabolism but, in addition, there are a number of other hydroxylated and oxidized metabolites. 

In addition to its classical role as regulator of calcium homeostasis, 1,25-dihydroxy vitamin D3 (calcitriol) displays immunosuppressive properties. Inhibition of T-lymphocyte proliferation seems to be mediated via regulation of CD80/86 costimulatory molecule expression on APCs. For clinical use as immunosuppressant, however, analogues of vitamin D3 that do not influence calcium metabolism are needed. 

Systemic regulators of osteoblast, osteocyte and osteoclast functions, and therefore of bone metabolism. The major bone-seeking hormones are parathyroid hormone (PIH), 1,25-dihydroxy vitamin D3 (calcitriol) and the various ex hormones. 

Vitamin D Is Metabolized to the Active Metabolite, Calcitriol, in Liver Kidney... 

Diesel B, Radermacher J, Bureik M, Bernhardt R, Seifert M, et al. 2005. VitaminD(3) metabolism in human glioblastoma multiforme functionality of CYP27B1 splice variants, metabolism of calcidiol, and effect of calcitriol. Clin Cancer Res 11 5370-5380. 

In addition to their involvement in excretion and metabolism, the kidneys also have endocrine functions. They produce the hormones erythropoietin and calcitriol and play a decisive part in producing the hormone angiotensin II by releasing the enzyme renin. Renal prostaglandins (see p. 390) have a local effect on Na resorption. 

Patients with chronic renal failure develop hyperphosphatemia, hypocalcemia, secondary hyperparathyroidism, and severe metabolic bone disease. The secondary hyperparathyroidism is thought to be due to hyperphosphatemia and decreased 1, 25-(OH)2 formation. Oral or intravenous l,25-(OH)2D3 (calcitriol) therapy along with oral phosphate-binding agents and calcium supplementation is effective in reducing the effects of renal osteodystrophy. 

Cholecalciferol is pure vitamin D3 derived from the ultraviolet conversion of 7-dehydrocholesterol to cholecalciferol. Ergocalciferol vitamin D2) is a sterol derived from yeast and fungal ergosterol. Calcitriol [Rocaltrol, 1,25-(0H)2D3] is the metabolically active vitamin D3 compound. Dihydrotachysterol is a synthetic compound that may act somewhat more quickly than either vitamin D2 or D3. 

Vitamin D3 is transported to liver where it undergoes a hydroxylation at C-25 into 1a,25-dihydroxyvitamin D3 (calcitriol) (Fig. 64). In the kidney, it undergoes further hydroxylations at different sites, depending on the serum Ca + concentration. The most biologically active metabolite of vitamin D3 is calcitriol, which plays important roles in the regulation of calcium and phosphorus metabolism. It is used for treating bone diseases, but is also involved in the cell proliferation and the inducement of cell differentiation [151]. 

The liver appears to be the principal organ for clearance. Excess vitamin D is stored in adipose tissue. The metabolic clearance of calcitriol in humans indicates a rapid turnover, with a terminal half-life measured in hours. Several of the l,25(OH)2D analogs are bound poorly by the vitamin D-binding protein. As a result, their clearance is very rapid, with a... 

In mild forms of malabsorption, vitamin D (25,000-50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, because no impairment of the renal metabolism of 25(OH)D to l,25(OH)2D and 24,25(OH)2D exists in these patients. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. However, calcifediol is no longer available. 

Finally, PTH helps increase the absorption of calcium from the gastrointestinal tract. This effect appears to be caused by the interaction between PTH and vitamin D metabolism. PTH increases the conversion of vitamin D to 1,25-dihydroxycholecalciferol (calcitriol).36 Calcitriol directly stimulates calcium absorption from the intestine. 

Calcifediol (25[OH]D3) may also be used to advantage. Calcifediol is less effective than calcitriol in stimulating intestinal calcium transport, so that hypercalcemia is less of a problem with calcifediol. Like dihydrotachysterol, calcifediol requires several weeks to restore normocalcemia in hypocalcemic individuals with chronic renal failure. Presumably because of the reduced ability of the diseased kidney to metabolize calcifediol to more active metabolites, high doses (50-100 Pg daily) must be given to achieve the supraphysiologic serum levels required for therapeutic effectiveness. 

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 hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metabolically active vitamin D hormone results from two successive hydroxylations in the liver at position 25 (- calcifediol) and in the kidney at position 1 (- calcitriol = vitamin D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca2+ and phosphate. Vitamin D hormone promotes enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of the increased Ca2+ and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vitamin D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vitamin D is given in liver disease, calcifediol may be indi-... 

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). 

Calcidiol la-hydroxylase also acts on 24-hydroxycalcidiol, yielding cal-citetrol indeed, it has a relatively low specificity and will act on any secosteroid with hydroxyl groups at C-3 and C-25. Calcitriol has a short metabolic half-life after injection of the order of 4 to 6 hours (Holick, 1990). But, under normal conditions, the regulation of its synthesis means that the plasma concentration remains fairly constant, depending on the state of calcium balance (Hewison et al., 2000). 

There is evidence that 24-hydroxycalcidiol has physiological functions distinct from those of calcitriol, and the regulation of the 24-hydroxylase suggests that it functions to provide a metabolically active product, as well as diverting calcidiol away from calcitriol synthesis (Henry, 2001). Studies of knockout mice lacking the 24-hydroxylase show that 24-hydroxycalcidiol has a role in both in-tramembranous bone formation during development and the suppression of parathyroid hormone secretion (St-Arnaud, 1999 van Leeuwen et al., 2001). 

Adipocytes have vitamin D receptors, and there is evidence that vitamin D may act as a suppressor of adipocyte development (Kawada et al., 1996). It has been suggested that vitamin D inadequacy may be a factor in the development of the metabolic syndrome ( syndrome X, the combination of insulin resistance, hyperlipidemia, and atherosclerosis associated with abdominal obesity). Sunlight exposure, and hence vitamin D status, may be a factor in the difference in incidence of atherosclerosis and myocardial infarction between northern and southern European countries in addition to effects on adipocyte development, calcitriol also enhances insulin secretion through induction of calbindin-D (Section 3.3.7.1), and there is some evidence vitamin D supplements can improve glucose tolerance (Boucher, 1998). 

Osteocalcin is induced in osteoblasts by calcitriol, and circulating osteocalcin can be used as an index of calcitriol action and metabolic bone disease. In rachitic children, the plasma concentration of osteocalcin is lower than in controls, and rises on therapy, remaining high until there is radiological evidence of cure. However, plasma osteocalcin can be undetectably low in normal subjects with adequate vitamin D status, so this does not provide a useful indication of deficiency (Greig et al., 1989). 

Figure 3.3. Metabolism of calciol to yield calcitriol and 24-hydroxycalcidiol.

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