Cholecalciferol (D3, dietary + cutaneous via UV-B on 7-dehydrocholesterol) and ergocalciferol (D2, fungal) → 25-hydroxyvitamin D (calcidiol) via hepatic CYP2R1 — the form measured clinically (reflects body stores; t½ ~3 weeks). 25-OH-D → 1,25-dihydroxyvitamin D (calcitriol, active hormone) via renal CYP27B1 (1α-hydroxylase) under PTH stimulation. Calcitriol → VDR → genomic effects (intestinal Ca/PO4 absorption + bone remodeling + immune modulation). Inactivation by CYP24A1 (24-hydroxylase). CKD-MBD: progressive CYP27B1 deficiency → low 1,25-D → secondary hyperPTH → bone disease + CV calcification. Treatment: calcitriol or paricalcitol (already-active vitamin D analogs) bypassing the failing renal step.
Organ Systems
endocrine
musculoskeletal
renal
Pathway Steps
7-dehydrocholesterol → cholecalciferol — via UV-B photolysis in skin (vitamin D3 endogenous synthesis). UV-B photolyzes 7-dehydrocholesterol in skin to previtamin D3, which thermally isomerizes to cholecalciferol — the endogenous source, limited by latitude, season, sunscreen, and skin pigmentation. Dietary D2/D3 bypass this step.
cholecalciferol → 25-hydroxycholecalciferol — via CYP2R1 (hepatic) — the calcidiol measured clinically. Hepatic CYP2R1 makes 25-hydroxyvitamin D (calcidiol) — the major circulating, storage form and the analyte measured to assess vitamin-D status (its long half-life reflects overall stores).
25-hydroxycholecalciferol → calcitriol — via CYP27B1 (renal 1α-hydroxylase) — PTH-activated; deficient in CKD. Renal CYP27B1 (1α-hydroxylase) makes active calcitriol, up-regulated by PTH and low phosphate and deficient in chronic kidney disease (renal osteodystrophy). Extra-renal CYP27B1 in macrophages explains the hypercalcemia of sarcoid/granulomatous disease.
calcitriol → inactive-24-hydroxy — via CYP24A1 (negative feedback). CYP24A1 inactivates calcitriol and 25-OH-D by 24-hydroxylation as negative feedback (induced by calcitriol and FGF23). Loss-of-function CYP24A1 mutations cause idiopathic infantile hypercalcemia from impaired vitamin-D breakdown.