Biological function and ?Metabolism of Vitamin D3

Discovery 

The presence of an antirachitic factor was reported in the 1910s. The chemical structure of vitamin D3 was determined in 1936 by Windaus.

Structure 

Vitamin D3 has a secosteroid structure with a broken C9–10 bond of the B ring in 7-dehydrocholesterol. Vitamin D3 is found in vertebrates as well as plankton. 

Properties 

Molecular formula: C27H44O, Mr 384.6. White crystal (fine needles). MP 84–88°C. UV λmax 265 nm. Insoluble in water. Soluble in organic solvents: ether, alcohol, etc. Oxidized by moist air. Heat and light labile.

Metabolism 

Vitamin D3 is only produced via the photochemical reaction of 7-dehydrocholestrol, the precursor of cholesterol, with ultraviolet light B (naturally with sunlight) and subsequent thermal isomerization. These two nonenzymatic chemical reactions are essential for vitamin D synthesis. In humans, these reactions occur in the skin. Vitamin D3 is converted to calcidiol, 25-hydroxyvitamin D3 (25(OH)D3) in the liver, which is the major circulating form of vitamin D.

The 25-hydroxylation reaction is catalyzed by several cytochrome P450 enzymes (CYPs) such as CYP2R1 (mammals), CYP27A1 (mammals), CYP3A4 (human), CYP2D25 (pig), CYP2C11 (male rat), and CYP2J3 (female rat) .The CYP2R1 and CYP27A1 are highly conserved across vertebrate species. Others are species-specific CYPs. CYP2R1 is the most important 25-hydroxylase in the human and mouse, and a genetic defect in CYP2R1 causes an abnormal calcium metabolism. However, the existence of multiple enzymes,especially CYP27A1, provides possibilities of compensation for 25(OH)D3 synthesis. 25(OH) D3 circulates in the blood, forming a complex with a specific vitamin D binding protein, DBP (mammals and birds). 25(OH)D3 is finally converted to the biologically active form of vitamin D3, calcitriol, by CYP27B1 in the kidney.

Biological function 

Target cells/tissues and functions 

An important role of vitamin D is to maintain the blood calcium concentration by promoting calcium absorption in the intestine and maintaining calcium and phosphate levels for bone formation. Vitamin D deficiency causes rickets in amphibians, reptiles, birds, and mammals.12 Vitamin D2 that is synthesized from ergosterol shows similar activity to vitamin D3 in the human and rat. However, vitamin D2 exhibits about 1%–2% of the biopotency of vitamin D3 in the chicken due to a difference in affinity to the vitamin D binding protein in blood between humans and chickens.

Use for diagnosis and treatment

Serum 25(OH)D3 measurement is clinically important in some disease diagnoses related to vitamin D status because 25(OH)D3 is the main circulating form of vitamin D. It is reported that vitamin D can decrease the risk of many chronic disorders, including cancers, autoimmune diseases, infectious diseases, and cardiovascular diseases. Vitamin D and its metabolites are presently used for the treatment of plaque psoriasis and some illnesses relating to calcium and phosphorus homeostasis, such as vitamin D deficiency, osteoporosis, and secondary hyperparathyroidism. Calcidiol, which does not require hepatic 25-hydroxylation, is available for patients with liver disease. 

Calcitriol, which does not require renal 1α-hydroxylation, is useful for patients with chronic renal failure or vitamin D-dependent rickets type I.