Vitamin D

Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium and phosphate, along with numerous other biological functions. In humans, the most important compounds within this group are vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol).

Unlike the other twelve vitamins, vitamin D is only conditionally essential, as with adequate skin exposure to the ultraviolet B (UVB) radiation component of sunlight there is synthesis of cholecalciferol in the lower layers of the skin's epidermis. Vitamin D can also be obtained through diet, food fortification and dietary supplements. For most people, skin synthesis contributes more than dietary sources. In the U.S., cow's milk and plant-based milk substitutes are fortified with vitamin D₃, as are many breakfast cereals. Government dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, given the potential for insufficient sunlight exposure due to urban living, cultural choices for the amount of clothing worn when outdoors, and use of sunscreen because of concerns about safe levels of sunlight exposure, including the risk of skin cancer.

Cholecalciferol is converted in the liver to calcifediol (also known as calcidiol or 25-hydroxycholecalciferol), while ergocalciferol is converted to ercalcidiol (25-hydroxyergocalciferol). These two vitamin D metabolites, collectively referred to as 25-hydroxyvitamin D or 25(OH)D, are measured in serum to assess a person's vitamin D status. Calcifediol is further hydroxylated by the kidneys and certain immune cells to form calcitriol (1,25-dihydroxycholecalciferol; 1,25(OH)₂D), the biologically active form of vitamin D. Calcitriol attaches to vitamin D receptors, which are nuclear receptors found in various tissues throughout the body.

The discovery of the vitamin in 1922 was due to an effort to identify the dietary deficiency in children with rickets. Adolf Windaus received the Nobel Prize in Chemistry in 1928 for his work on the constitution of sterols and their connection with vitamins. Present day, government food fortification programs in some countries and recommendations to consume vitamin D supplements are intended to prevent or treat vitamin D deficiency rickets and osteomalacia. There are many other health conditions linked to vitamin D deficiency. However, the evidence for the health benefits of vitamin D supplementation in individuals who are already vitamin D sufficient is unproven.

Several forms (vitamers) of vitamin D exist, with the two major forms being vitamin D₂ or ergocalciferol, and vitamin D₃ or cholecalciferol. The common-use term "vitamin D" refers to both D₂ and D₃, which were chemically characterized, respectively, in 1931 and 1935. Vitamin D₃ was shown to result from the ultraviolet irradiation of 7-dehydrocholesterol. Although a chemical nomenclature for vitamin D forms was recommended in 1981, alternative names remain commonly used.

Chemically, the various forms of vitamin D are secosteroids, meaning that one of the bonds in the steroid rings is broken. The structural difference between vitamin D₂ and vitamin D₃ lies in the side chain: vitamin D₂ has a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D analogues have also been synthesized.

The active vitamin D metabolite, calcitriol, exerts its biological effects by binding to the vitamin D receptor (VDR), which is primarily located in the nuclei of target cells. When calcitriol binds to the VDR, it enables the receptor to act as a transcription factor, modulating the gene expression of transport proteins involved in calcium absorption in the intestine, such as TRPV6 and calbindin. The VDR is part of the nuclear receptor superfamily of steroid hormone receptors, which are hormone-dependent regulators of gene expression. These receptors are expressed in cells across most organs. VDR expression decreases as age increases.

Activation of VDR in the intestine, bone, kidney, and parathyroid gland cells plays a crucial role in maintaining calcium and phosphorus levels in the blood, a process that is assisted by parathyroid hormone and calcitonin, thereby supporting bone health. VDR also regulates cell proliferation and differentiation. Additionally, vitamin D influences the immune system, with VDRs being expressed in several types of white blood cells, including monocytes and activated T and B cells.