SYNTHESIS OF 1,25(OH)2D3 FROM VITAMIN D3
Vitamin D3 (cholecalciferol) is taken in the diet (from fortified dairy products and fish oils) or is synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. The vitamin D produced by 7-dehydrocholesterol depends on the intensity of UV irradiation which varies with season and latitude.
Sunscreen and clothing have been reported to prevent the conversion of 7-dehydrocholesterol to vitamin D3 . In order to be biologically active and affect mineral metabolism and to have effects on numerous other diverse physiological functions including inhibition of growth of cancer cells and protection against certain immune mediated disorders, vitamin D most be converted to its active form.
Vitamin D is transported in the blood by the vitamin D binding protein (DBP, a specific binding protein for vitamin D and its metabolites in serum) to the liver. In the liver vitamin D is hydroxylated at C-25 by one or more cytochrome P450 vitamin D 25 hydroxylases (including CYP2R1, CYP2D11 and CYP2D25), resulting in the formation of 25-hydroxyvitamin D3 (25(OH)D3).
It has been suggested that CYP2R1 is the key enzyme required for 25 hydroxylation of vitamin D since a homozygous mutation of the CYP2R1 gene was found in a patient with low circulating levels of 25(OH)D3 and classic symptoms of vitamin D deficiency.
25(OH)D3, the major circulating form of vitamin D, is transported by the DBP to the kidney. In the kidney, magalin, a member of the LDL receptor superfamily, plays an essential role in endocytic internalization of 25(OH)D3.
In the proximal renal tubule 25(OH)D3 is hydroxylated at the position of carbon 1 of the A ring, resulting in the hormonally active from of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) which is responsible for most, if not all of the biological actions of vitamin D.
The cytochrome P450 monooxygenase 25(OH)D 1Î± hydroxylase (CYP27B1; 1Î±(OH)ase) which metabolizes 25(OH)D3 to 1,25(OH)2D3 is present predominantly in kidney. This enzyme is also found in extrarenal sites including placenta, monocytes and macrophages.
As with all mitochondrial P450 containing enzymes, during the 1Î±(OH)ase reaction electrons are transferred from NADPH to NADPH-ferrodoxinreductase through ferrodoxin. Inactivating mutations in the 1Î±(OH)ase gene result in vitamin D dependency rickets (VDDR) type 1 in spite of normal intake of vitamin D, indicating the importance of the 1Î±(OH)ase enzyme.
Type 1 vitamin D dependent rickets is characterized by growth failure, hypocalcemia, elevated PTH, muscle weakness and radiologic findings typical of rickets.
- Calcium regulation in the human body.The role of vitamin D is shown in orange.
- Liver hydroxylation of cholecalciferol to Calcifediol
- Kidney hydroxylation of calcifediol to calcitriol
- Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcifediol. Circulating calcifediol may then be converted into calcitriol, the biologically active form of vitamin D, in the kidneys. Following the final converting step in the kidney, calcitriol is released into the circulation. By binding to vitamin D-binding protein, a carrier protein in the plasma, calcitriol is transported to various target organs. In addition to the kidneys, calcitriol is also synthesized by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders by stimulating the innate immune system.
- Whether it is made in the skin or ingested, cholecalciferol is hydroxylated in the liver at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcifediol or 25(OH)D). This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase which is produced by hepatocytes. Once made, the product is released into the plasma, where it is bound to an Î±-globulin, vitamin D-binding protein.
- Calcifediol is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-Î± position (lower right of the molecule) to form calcitriol (1,25-dihydroxycholecalciferol and abbreviated to 1,25(OH)2D). This product is a potent ligand of the vitamin D receptor, which mediates most of the physiological actions of the vitamin. The conversion of calcifediol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, the levels of which are increased by parathyroid hormone (and additionally by low calcium or phosphate).
Food sources and skin synthesis
Vitamin D, synonym calciferol, often referred to as the â€˜sunshine vitaminâ€™, is essential for life in all higher organisms. It is a secosteroid hormone which exists in two forms: ergocalciferol (vitamin D2), found in fungi; and cholecalciferol (vitamin D3), found in vertebrates. Only a few foods contain appreciable amounts of vitamin D.
Vitamin D can also be synthesized in human skin in response to sunlight exposure and is the strongest factor influencing vitamin D status Solar ultraviolet-B (UVB) radiation (290â€“315 nm) initiates cutaneous synthesis of vitamin D by the photo conversion of 7-dehydrocholesterol to pre-vitamin D3. Then, over a period of 1â€“2 days at body temperature, pre-vitamin D3 isomerizes to D3; once formed, it is sterically unacceptable and ejected from the cell membrane into the extracellular space and then into circulation. It is important to note that prolonged exposure to UVB light does not increase pre-vitamin D3 production, but rather is photo degraded to biologically inert isomers.