Figure 1.

Vitamin D metabolism and the sites of vitamin D resistance acquirement. Vitamin D₃ is mainly produced in the skin through solar ultraviolet-B (UVB) radiation and gets transported through blood by binding to vitamin D binding protein (DBP). The liver is the systemic production site of 25(OH)D₃ via the enzymes CYP2R1, CYP27A1 or CYP27B1. 25(OH)D₃ then gets converted to the active hormone 1,25(OH)₂D₃ by a second hydroxylation which occurs mainly in the kidneys or in other tissues through paracrine production. 1,25(OH)₂D₃ binds to the vitamin D receptor (VDR) to promote intestinal calcium (Ca) absorption and other Ca-mobilization pathways (e.g. in bone), so that ionized Ca levels in serum rise. The paraythroid glands sense Ca²⁺ levels, and secrete parathyroid hormone (PTH). PTH in turn promotes the production of 1,25(OH)₂D₃, e.g. by inhibiting CYP24A1 which catalyzes the first degradation step of 1,25(OH)₂D₃. Besides 1,25(OH)₂D₃, there are other vitamin D3-derived hydroxy-metabolites that exert hormone-like actions. For example, skin also expresses CYP11A1, which promotes the conversion of vitamin D₃ into 20(OH)D₃, which has non-calcemic biological effects, for example on immune cells. The blue flashes show where polymorphisms can interfere with normal vitamin D metabolism, building the basis for the development of acquired vitamin D resistance. Additional factors that impair vitamin D signaling are highlighted in blue boxes.