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Vitamin D Production

Vitamin D₃ (cholecalciferol) is produced in the epidermal layer of the skin from 7-dehydrocholesterol (Fig. 1). This is a nonenzymatic process by which, under the influence of solar or UVB irradiation (optimal wavelength 280–320 μm), the B ring of 7-dehydrocholesterol is opened to form pre-D₃, lumisterol and tachisterol. Pre-D₃ is then isomerized in a thermo-sensitive process to form D₃. The production rate of D₃ depends upon the intensity of the UVB (time of day, season of the year, latitude), aging, sun screen use, and degree of skin pigmentation [15, 16]. African Americans may need 5–10 times longer UVB light exposure compared to Caucasians to produce the same amount of vitamin D in the skin, thus explaining why they are at much higher risk for vitamin D deficiency. Continued exposure to sunlight would increase the production of D₃ without reaching toxic amounts because once a maximum level is achieved Pre-D₃ will be converted into lumisterol and tachisterol.

Vitamin D₂ (ergocalciferol) is produced by UVB irradiation of ergosterol in plants and fungi (Fig. 1). The chemical structure of D₂ differs from that of D₃ because of a double bond between C22 and C23 and a methyl group at C24 in the side chain.

Foods, with the exception of wild caught salmon and other oily fish, cod liver oil, and mushroom, contain very little vitamin D unless fortified.

Fig. 1. Synthesis and metabolism of vitamin D. Upon exposure to solar ultraviolet B (UBV) radiation, ergosterol and 7-dehydrocholesterol are converted to previtamin D₂ (PreD₂) and previtamin D₃ (PreD₃), respectively, and immediately after to vitamin D₂ and D₃ in a heath-dependent reaction. In the liver, vitamin D is hydroxylated in position 25 by the CYP2R1 enzyme to form 25-hydroxyvitamin D 25(OH)D, which in the kidney is further hydroxylated in position 1α by the CYP27B1enzyme to form 1,25(OH)₂D. The CYP27B1 activity is stimulated (+) by PTH and inhibited (–) by calcium (Ca), phosphorus (P), fibroblast growth factor 23 (FGF23), and 1,25(OH)₂D itself. 1,25(OH)₂D decreases its synthesis by inhibiting the CYP27B1 and increases its catabolism to 1,24,25(OH)₃D by stimulating the activity of CYP24A1. Ca, P, and FGF23 also stimulate the CYP24A1 enzyme, thus shunting the substrate 25(OH)D away from the CYP27B1 enzyme.

Vitamin D Metabolism

Vitamin D (D refers to either D₂ or D₃) produced in the skin or ingested with food reaches the circulation where it binds to the serum vitamin D binding protein (DBP) and reaches the sites of storage (mainly fat and muscle) and other tissues, especially the liver, where it is converted to 25-hydroxyvitamin D (25[OH]D; calcifediol; Fig. 1) by the action of the CYP2R1 25-hydroxylase enzyme, a member of the cytochrome P450 oxidase superfamily. The production of 25(OH)D is largely dependent upon the amount of its substrate, vitamin D. 25(OH)D is the major circulating form of vitamin D and is biologically inactive unless its serum concentration reaches toxic levels following the ingestion of large amount of vitamin D. Its measurement in the serum is widely used to assess a person’s vitamin D status [17].

25(OH)D is further hydroxylated in the proximal renal tubular epithelial cells by the CYP27B1 1α-hydroxylase to form 1,25(OH)₂D (calcitriol), the active vitamin D metabolite (Fig. 1). The 1,25(OH)₂D produced in the kidney is involved in the control of calcium and bone homeostasis. Unlike the hepatic CYP2R1, the renal CYP27B1 is tightly regulated mainly by PTH, the phosphaturic hormone fibroblast growth factor 23 (FGF23), and by 1,25(OH)₂D itself (Fig. 1). PTH stimulates and FGF23 and 1,25(OH)₂D inhibit the CYP27B1 enzyme. Moreover, increased serum calcium and phosphate inhibit the CYP27B1 activity by suppressing PTH and FGF23 respectively. The precise mechanisms by which PTH stimulates and FGF23 inhibits the CYP27B1 enzyme are still unclear. 1,25(OH)₂D limits the CYP27B1 activity by inhibiting and stimulating the production of PTH and FGF23, respectively, and also by decreasing its release into the circulation by different mechanisms (Fig. 2): (i) direct inhibition of CYP27B1 expression in proximal renal tubular epithelial cells; (ii) activation of the CYP24A1 24-hydroxylase enzyme, which accelerates the catabolism of 1,25 (OH)₂D to 1,24,25 (OH)₃D and favors the synthesis of 24,25(OH)₂D, thus shunting the substrate 25(OH)D away from the CYP27B1 enzyme. Some data suggest that 1,24,25 (OH)₃D and possibly also 24,25(OH)₂D have biologic activity.

Fig. 2. Integrated hormonal regulation of extracellular (ECF) calcium (Ca) homeostasis. A decreased (↓) ECF Ca results in increased PTH secretion from the parathyroid glands via the calcium sensing receptor (CaSR; a). The increased PTH can augment renal Ca reabsorption (b); in addition, with reduced ECF Ca, the CaSR is not activated to cause calciuria. PTH can also increase renal synthesis of 1,25(OH)₂D from 25(OH)D (c). The 1,25(OH)₂D produced can enhance intestinal absorption of Ca (d), and both PTH and 1,25(OH)₂D can resorb bone (e), thus increasing Ca release from bone. The resulting increase (↑) of ECF Ca (f) inhibits (┤) additional PTH release (g). 1,25(OH)₂D can also contribute to the inhibition of further PTH release (h) and can stimulate FGF23 release from bone (i). FGF23 in turn can inhibit further 1,25(OH)₂D production in the kidney (j). PTH may also stimulate FGF23 (k), which may then limit further PTH release (l).

The CYP27B1 enzyme is also present in several other tissues where 1,25(OH)₂D is likely to have paracrine/autocrine functions including: (i) epithelial cells (skin, breast, lung and prostate): (ii) endocrine glands (parathyroids, thyroid, pancreatic islets, testis, ovary and placenta); (iii) cells involved in the immune response (T and B lymphocytes, macrophages and dendritic cells); (iv) osteoclasts and osteoblasts; and (v) tumors originating from these cells [18]. The regulation of the extrarenal CYP27B1 appears to be primarily controlled by the availability of the 25(OH)D substrate to the enzyme and by various cytokines.

Vitamin D and its metabolites are bound in the serum to the DBP, a member of the albumin family of proteins [19]. DBP has a high capacity, being saturated less than 5% in humans, and is bound with higher affinity by 25-hydroxylated metabolites. Internalization of DBP-bound 25(OH)D is mediated by LDL-like co-receptor molecules megalin and cubulin embedded in the plasma membrane of the proximal tubular renal epithelial cells [20]. Intracellular DBP chaperones mediate the return into the circulation. Other plasma membrane-anchored acceptor molecules for DBP, similar to those present in the renal tubule, likely exists to allow vitamin D metabolites to gain access inside their target cells and reach their intracellular site (nucleus, inner mitochondrial membrane).

Vitamin D Analogs

In addition to the naturally occurring vitamin D metabolites, several vitamin D analogs (1α[OH]D₃ [alfacalcidiol], 1α[OH]D₂ [doxercalciferol], dihydrotachisterol, 26,27F_6–1,25[OH]₂D₃ [falecalcitriol], calcipotriol, maxacalcitol, paracalcitol, and eldecalcitol) have been synthesized, but only a few are approved in different countries for treatment of several conditions, including hypoparathyroidism, osteoporosis, secondary hyperparathyroidism in chronic kidney diseases, and psoriasis. Table 1 summarizes the characteristics of the vitamin D metabolites most widely used in clinical practice.

Mechanism of Action

The mechanism of action of 1,25(OH)₂D is similar to that of other steroid hormones. All genomic actions are mediated by binding to the vitamin D receptor (VDR), which is expressed in most tissues of the body. The VDR is a transcription factor with substantial homology with other members of the steroid hormone receptor superfamily [21]. VDR forms a heterodimer with the retinoid X receptor and binds to specific DNA sequences (VDR response elements; VDRE) to activate or inhibit transcription. The availability of modern techniques, like microarray, has expanded our knowledge of the mechanism of action of the VDR/retinoid X receptor complex at the genomic level [22]. Hundreds of genes and 1,000 of VDREs have been identified in target cells, which are involved in the classical skeletal effects of 1,25(OH)₂D (calcium absorption, calcium and phosphate metabolism, bone matrix mineralization and bone resorption) as well as in several extraskeletal effects.

1,25(OH)₂D also exerts nongenomic, rapid effects, such as the rapid stimulation of intestinal calcium transport and effects at the level of chondrocytes in the growth plate and keratinocytes in the skin. The receptors for these nongenomic actions are located in the membrane within caveolae/lipid rafts, which after ligand binding activate ion channel, kinases, and phosphatases [23].

Table 1. Vitamin D metabolites most widely used in clinical practice