**3. Vitamin D metabolism**

Vitamin D is a prohormone. Its active form, 1a 25‐dihydroxyvitamin D (1,25(OH)2D), plays an essential role influencing various metabolic pathways [7, 21, 26–30].

Skin synthesis from sunlight exposure (wavelength, 290–315 nm) contributes to 80–90% of vitamin D production in humans under natural conditions (D3—cholecalciferol) [17]. UV‐B irradiation of skin triggers photolysis of 7‐dehydrocholesterol (provitamin D3) in the plasma membrane of human skin keratinocytes [3], which is then rapidly converted to vitamin D3 by the skin's temperature (**Figure 1**) [7].

**Figure 1.** Vitamin D synthesis and metabolism [17].

The dietary supply of vitamin D (D2—ergocalciferol) contributes 10–20% to the total amount of vitamin D in the body [31].

D3 from the skin and D2 from the diet undergo two sequential hydroxylations: 25 hydroxylation in the liver followed by 1,25‐dihydroxylation in the kidney by 1‐alpha hydroxylase (CYP27B1) (**Figure 1**). The major circulating metabolite of vitamin D is 25(OH)D, which should be measured clinically to assess vitamin D status, reflecting both intake and endogenous pro‐ duction [15, 31, 32]. 1,25(OH)2D3 is the biologically active form. The hydroxylation of 25(OH)D to its biologically active form is under control of parathyroid hormone (PTH) [7, 15].

The majority of 25(OH)D and 1,25(OH)2D3 in the circulation is bound to vitamin D‐binding protein (DBP) (80–90%) and albumin (1–20%), while a small fraction is free. Production and levels are regulated by a feedback loop that includes serum PTH, calcium, and phosphate [3, 10, 16, 32].

Most of the known biological effects of 1,25(OH)2D3 are mediated through the vitamin D3 receptor (VDR), a member of the superfamily of nuclear hormone receptors, which mediates transcriptional gene regulation [3, 7, 33–35].

1,25(OH)2D3 enters the cell and interacts with its nuclear VDR. It then forms a heterodimeric complex with the retinoic acid X receptor. Once the receptor complex binds to vitamin D‐ responsive elements, a variety of transcriptional factors bind to it, resulting in gene expression [17] (**Figure 2**).

**Figure 2.** Cellular effects of vitamin D.

membrane of human skin keratinocytes [3], which is then rapidly converted to vitamin D3 by

The dietary supply of vitamin D (D2—ergocalciferol) contributes 10–20% to the total amount

D3 from the skin and D2 from the diet undergo two sequential hydroxylations: 25 hydroxylation in the liver followed by 1,25‐dihydroxylation in the kidney by 1‐alpha hydroxylase (CYP27B1) (**Figure 1**). The major circulating metabolite of vitamin D is 25(OH)D, which should be measured clinically to assess vitamin D status, reflecting both intake and endogenous pro‐ duction [15, 31, 32]. 1,25(OH)2D3 is the biologically active form. The hydroxylation of 25(OH)D

The majority of 25(OH)D and 1,25(OH)2D3 in the circulation is bound to vitamin D‐binding protein (DBP) (80–90%) and albumin (1–20%), while a small fraction is free. Production and levels are regulated by a feedback loop that includes serum PTH, calcium, and phosphate [3,

Most of the known biological effects of 1,25(OH)2D3 are mediated through the vitamin D3 receptor (VDR), a member of the superfamily of nuclear hormone receptors, which mediates

1,25(OH)2D3 enters the cell and interacts with its nuclear VDR. It then forms a heterodimeric complex with the retinoic acid X receptor. Once the receptor complex binds to vitamin D‐

to its biologically active form is under control of parathyroid hormone (PTH) [7, 15].

the skin's temperature (**Figure 1**) [7].

6 A Critical Evaluation of Vitamin D - Clinical Overview

**Figure 1.** Vitamin D synthesis and metabolism [17].

transcriptional gene regulation [3, 7, 33–35].

of vitamin D in the body [31].

10, 16, 32].

Over 200 genes are regulated by 1,25(OH)2D3. These include genes directly or indirectly responsible for renin and insulin production [15, 36], cytokine release [34], and vascular smooth muscle cell (VSMC) and cardiomyocyte proliferation [37].

1,25(OH)2 is also involved in non‐genomic mediated intracellular signaling demonstrating immunomodulatory, antiproliferative, and prodifferentiative activities in experimental settings [17, 31, 38].
