Vitamin D3 (cholecalciferol), synthesised in human skin by ultraviolet radiation action on 7-dehydrocholesterol, does not possess any biological activity. Vitamin D hormonal activity requires hydroxylation at the 25 and 1-alpha positions by cytochrome P450 enzymes CYP2R1 and CYP27B1 respectively.
Vitamin D 25-hydroxylase (CYP2R1) catalyses the hydroxylation of vitamin D3 to calcidiol (CDL). Subsequent 1-alpha-hydroxylation of CDL produces calcitriol (CTL). CTL binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis, cellular differentiation and proliferation.
Defects in CYP2R1 can cause rickets, vitamin D-dependent 1B (VDDR1B; MIM:600081), a disorder caused by a selective deficiency of the active form of vitamin D (CTL) resulting in defective bone mineralization and clinical features of rickets (Pikuleva et al. 2013).