Vitamin D

Vitamin D is not strictly a vitamin, rather it is the precursor of one of the hormones involved in the maintenance of calcium homeostasis and the regulation of cell proliferation and differentiation, where it has both endocrine and paracrine actions. Dietary sources are relatively unimportant compared with endogenous synthesis in the skin by photolysis of 7-dehydrocholesterol; problems of deficiency arise when there is inadequate exposure to sunlight. The deficiency diseases (rickets in children and osteomalacia in adults) are therefore largely problems of temperate and subarctic regions, although cultural factors that result in little exposure to sunlight may also cause problems in subtropical and tropical areas. There are few foods that are rich sources of vitamin D. It is generally accepted that, for people with inadequate exposure to sunlight (young children and the house-bound elderly), supplements are necessary to maintain adequate status. Excessively high intakes of vitamin D are associated with hypercalcemia and calcinosis.

Although the pioneering studies of Chick and others during the 1920s clarified the dual roles of sunlight exposure to promote endogenous synthesis and dietary sources of the vitamin, it was not until high specific activity [3H]vitamin D became available in the 1960s that the onward metabolism of vitamin D to the active metabolite, calcitriol, was discovered, and its mechanism of action elucidated, largely by Kodicek and coworkers in Cambridge and DeLuca and coworkers in Wisconsin. Calcitriol acts as a steroid hormone, binding to a nuclear receptor protein in target tissues and regulating gene expression. As a result of studies of the distribution of calcitriol receptors and the induced proteins, a number of functions have been discovered for the vitamin other than in the maintenance of calcium balance, including roles in cell proliferation and differentiation, in the modulation of immune system responses, and in the secretion of insulin and thyroid and parathyroid hormones.

More recent studies, during the 1990s, have shown that calcitriol also has rapid actions, acting via cell surface G-protein receptors linked to both adenylate cyclase and phospholipase cascade systems.

3.1 VITAMIN D VITAMERS, NOMENCLATURE, AND UNITS OF ACTIVITY

Two compounds have the biological activity of vitamin D: cholecalciferol, which is the compound formed in the skin, and ergocalciferol, which is synthesized by ultraviolet (UV) irradiation of ergosterol (see Figure 3.1). The name vitamin D1 was originally given to the crude product of irradiation of ergosterol, which contained a mixture of ergocalciferol with inactive lumisterol (an isomer of ergosterol) and suprasterols. When ergocalciferol was identified as the active compound, it was called vitamin D2. Later, when cholecalciferol was identified as the compound formed in the skin and found in foods, it was called vitamin D3. Vitamin D is a secosteroid -i.e., a steroid in which the B-ring has undergone cleavage, followed by rotation of the A-ring (see Figures 3.1 and 3.2). The numbering of carbon atoms in the vitamin follows that of the parent steroid nucleus, and, more confusingly, the assignation of positions of substituents above or below the plane of the ring also follows that of the parent steroid. This means that the 1-hydroxylated derivative, which actually has the f-configuration, is correctly referred to as 1a-hydroxy. As discussed in Section 3.2, vitamin D undergoes hydroxylation to the metabolically active 1,25-dihydroxy derivative, and a number of abbreviations for the various hydroxylated derivatives are used in the literature. The recommended nomenclature for the metabolites is shown in Table 3.1.

Figure 3.1. Vitamin D vitamers. Relative molecular masses (Mr): calciol, 384.6; ercalciol, 396.6.

Table 3.1 Nomenclature of Vitamin D Metabolites

Trivial Name

Recommended Name

Abbreviation

Mr

Vitamin D3

Cholecalciferol

CaIcioI

384.6

25-Hydroxycholecalciferol

CaIcidioI

25(OH)D3

400.6

1 a-Hydroxycholecalciferol

1(S)-HydroxycaIcioI

1a(OH)D3

400.6

24,25-Dihydroxycholecalciferol

24(R)-Hydroxycalcidiol

24,25(OH)2D3

416.6

1,25-Dihydroxycholecalciferol

CaIcitrioI

1,25(OH)2D3

416.6

1,24,25-Trihydroxycholecalciferol

CaIcitetroI

1,24,25(OH)3D3

432.6

Vitamin D2

Ergocalciferol

ErcaIcioI

396.6

25-Hydroxyergocalciferol

ErcaIcidioI

25(OH)D2

412.6

24,25-Dihydroxyergocalciferol

24(R)-Hydroxyercalcidiol

24,25(OH)2D2

428.6

1,25-Dihydroxyergocalciferol

ErcaIcitrioI

1,25(OH)2 D2

428.6

1,24,25-Trihydroxyergocalciferol

Ercalcitetrol

1,24,25(OH)3D2

444.6

Abbreviations shown in column 3 are not recommended, but are frequently used in the liter

ature.

Before the preparation of crystalline cholecalciferol, the standard for biological activity of vitamin D was a solution of irradiated ergosterol (and hence ergocalciferol). The (obsolete) international unit (iu) of vitamin D activity is equivalent to 25 ng (65 pmol) of cholecalciferol. One microgram of cholecalciferol is equivalent to 40 iu (1 nmol is 104 iu). Cholecalciferol and ergo-calciferol are not equipotent, and the relative biological activities of the two vitamers differ in different species. In most species (including human beings), cholecalciferol causes a greater increase in the circulating concentration of the 25-hydroxy-derivative than does ergocalciferol, because of faster metabolic clearance of ergocalciferol than cholecalciferol. In the rat, by contrast, there is metabolic discrimination against cholecalciferol in favor of ergocalciferol. As far as is known, the active metabolites (calcitriol and ercalcitriol) are equipo-tent and bind to calcitriol receptors in target tissues (Section 3.3.3.1) with equal affinity (Horst et al., 1982; Trang et al., 1998).

3.2 METABOLISM OF VITAMIN D

Synthetic ergocalciferol is used for enrichment and fortification of foods; its metabolic fate is the same as that of dietary cholecalciferol. Except where there are known to be differences between the two vitamers, it is assumed that all of the following discussion applies equally to ergocalciferol and cholecalciferol. There are few rich dietary sources of vitamin D, and the major source is usually photosynthesis in the skin. Dietary vitamin D is absorbed in chylomicrons and taken up rapidly by the liver as chylomicron remnants are cleared from

Table 3.2 Plasma Concentrations of Vitamin D Metabolites nmol/L

Cholecalciferol 24-Hydroxycalcidiol Calcitriol Calcidiol

Adults, summer Adults, winter Adults with osteomalacia Children, summer Children, winter Children with rickets Risk of hypercalcemia

0.038-0.144

37-87

20-45

50-100

27-52

>400

the circulation. By contrast, vitamin D synthesized in the skin is bound to plasma vitamin D binding protein (Section 3.3.2.7) and is metabolized more gradually.

Both dietary and endogenously synthesized vitamin D undergo 25-hy-droxylation in the liver to yield calcidiol (25-hydroxycholecalciferol), which is the main circulating form of the vitamin. This undergoes 1-hydroxylation in the kidney to produce the active hormone calcitriol (1,25-dihydroxy-cholecalciferol) or 24-hydroxylation in the kidney and other tissues to yield 24-hydroxycalcidiol (24,25-dihydroxycholecalciferol).

Unlike the other fat-soluble vitamins, there is little 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.

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