Vitamin D in Clinical Medicine. Группа авторов
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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, 26,27F6–1,25[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
Role of Gut, Kidney, and Bone in Maintaining Calcium Homeostasis
Fluxes of Ca across bone, gut, and kidney each play a major role in assuring Ca homeostasis.
Gut
In a typical adult, if 1,000 mg of Ca are ingested in the diet per day, approximately 200 mg will be absorbed in the intestine, and about 10 g of Ca will be filtered daily through the kidney. The majority of the Ca will be reabsorbed, with about 5 mmol (200) mg being excreted in the urine. The normal 24-h excretion of Ca may, however, vary between 2.5 and 7.5 mmol (100 and 300 mg per day). If bone turnover is “in balance,” approximately