**4. Synthesis and metabolism**

Vitamin D, either endogenously produced (vitamin D3) or ingested (vitamin D2 or vitamin D3), must be activated in order to produce its effects [5]. This biological activation is performed in a multi-step process (**Figure 2**).

Firstly, UVB radiation penetrates the epidermis and stimulates the conversion of 7-dehydrocholesterol (7-DHC) into pre-vitamin D3 [18] which undergoes thermal isomerization through a sigmatropic hydride shift into vitamin D3 [13].

Secondly, vitamin D2 or D3 is specifically translocated by DBP into circulation and then to the liver for hydroxylation at carbon-25 to form 25-hydroxyvitamin D [25(OH)D] mainly by two cytochrome P-450 enzymes (CYP2R1 and CYP27A1) [5].

**Figure 2.** *A diagram illustrating the different sources and synthesis of vitamin D.*

[25(OH)D] is an inactive and the most abundant circulating form of vitamin D, and it is generally measured when assessing vitamin D status which has a circulating half-life of about 15 days [2].

Thirdly, 1,25-dihydroxyvitamin D [1,25(OH)2D], the biologically active form of vitamin D, is generated through second hydroxylation that takes place in the kidney [6] by the enzyme cytochrome P-450 (CYP27B1) monooxygenase 25(OH)D-1-αhydroxylase [13] [1,25(OH)2D], which serves as a hormone to regulate a variety of cellular functions in other organs or acts inside the kidneys in an autocrine and/or paracrine fashion [5]. Several factors regulate the levels of [1,25(OH)2D], 25(OH) D-1-α-hydroxylase (whose hydroxylation is activated by PTH), calcitonin (which is inhibited by serum levels of calcium), phosphorus, and [1,25(OH)2D] itself [19].

Finally, [1,25(OH)2D] enters the cell by diffusion and binds and activates the VDR [20].
