Cholecalciferol, also known as vitamin D<sub>3</sub>, colecalciferol or calciol, is a skin-made vitamin D that is found in certain foods and used as a dietary supplement. It was first described in 1936, and is on the World Health Organization's List of Essential Medicines. In 2023, it was the 68th most commonly prescribed medication in the United States, with more than 9million prescriptions, and is available as a generic medication.
Cholecalciferol is synthesised in the skin following sunlight exposure. It is then converted in the liver to calcifediol (25-hydroxycholecalciferol D), which is further converted in the kidney to calcitriol (1,25-dihydroxycholecalciferol D). Cholecalciferol is present in food such as fatty fish, beef liver, eggs, and cheese. In some countries, cholecalciferol is also added to products like plants, cow milk, fruit juice, yogurt, and margarine. It is also used in the management of familial hypophosphatemia, hypoparathyroidism that is causing low blood calcium, and Fanconi syndrome. Vitamin-D supplements may not be effective in people with severe kidney disease. Normal doses, IU per day, are safe in pregnancy.
Vitamin D deficiency
Cholecalciferol is a form of vitamin D which is naturally synthesized in skin and functions as a pro-hormone, being converted to calcitriol. This is important for maintaining calcium levels and promoting bone health and development.
- In the EU: () for all people older than 1 year and () for infants aged 7–11 months, assuming minimal cutaneous vitamin D synthesis.
- In the UK: a 'Safe Intake' (SI) of () for infants < 1 year (including exclusively breastfed infants) and an SI of () for children aged 1 to <4 years; for all other population groups aged 4 years and more (including pregnant/lactating women) a Reference Nutrient Intake (RNI) of ().
Low levels of vitamin D<sub>3</sub> are more commonly found in individuals living in northern latitudes or with other reasons for a lack of regular sun exposure, including being housebound, frail, elderly, or obese, having darker skin, and wearing clothes that cover most of the skin. Supplements are recommended for these groups of people. Patients with severe vitamin D deficiency will require treatment with a loading dose; its magnitude can be calculated based on the actual serum 25-hydroxy-vitamin D level and body weight.
There are conflicting reports concerning the relative effectiveness of cholecalciferol (D<sub>3</sub>) versus ergocalciferol (D<sub>2</sub>), with some studies suggesting less efficacy of D<sub>2</sub>, and others showing no difference. There are differences in absorption, binding and inactivation of the two forms, with evidence usually favoring cholecalciferol in raising levels in blood, although more research is needed.
A much less common use of cholecalciferol therapy in rickets utilizes a single large dose and has been called stoss therapy. Treatment is given either orally or by intramuscular injection of () to ( = ), in a single dose, or sometimes in two to four divided doses. There are concerns about the safety of such large doses.
Other diseases
A meta-analysis of 2007 concluded that daily intake of of vitamin D<sub>3</sub> could reduce the incidence of colorectal cancer with minimal risk. Also a 2008 study published in Cancer Research has shown the addition of vitamin D<sub>3</sub> (along with calcium) to the diet of some mice fed a regimen similar in nutritional content to a new Western diet with 1000 IU cholecalciferol per day prevented colon cancer development. In humans, with daily, there was no effect of cholecalciferol supplements on the risk of colorectal cancer.
Supplements are not recommended for prevention of cancer as any effects of cholecalciferol are very small. Although correlations exist between low levels of blood serum cholecalciferol and higher rates of various cancers, multiple sclerosis, tuberculosis, heart disease, and diabetes, the consensus is that supplementing levels is not beneficial. It is thought that tuberculosis may result in lower levels. It is not entirely clear, however, how the two are related.
Biochemistry
Structure
Cholecalciferol is one of the five forms of vitamin D. Cholecalciferol is a secosteroid, that is, a steroid molecule with one ring open.
Mechanism of action
By itself cholecalciferol is inactive. It is converted to its active form by two hydroxylations: the first in the liver, by CYP2R1 or CYP27A1, to form 25-hydroxycholecalciferol (calcifediol, 25-OH vitamin D<sub>3</sub>). The second hydroxylation occurs mainly in the kidney through the action of CYP27B1 to convert 25-OH vitamin D<sub>3</sub> into 1,25-dihydroxycholecalciferol (calcitriol, 1,25-(OH)<sub>2</sub>vitamin D<sub>3</sub>). All these metabolites are bound in blood to the vitamin D-binding protein. The action of calcitriol is mediated by the vitamin D receptor, a nuclear receptor which regulates the synthesis of hundreds of proteins and is present in virtually every cell in the body. This results in the opening of the vitamin precursor B-ring through a conrotatory pathway making previtamin D<sub>3</sub> (pre-cholecalciferol). In a process which is independent of UV light, the pre-cholecalciferol then undergoes a [1,7] antarafacial sigmatropic rearrangement and therein finally isomerizes to form vitamin D<sub>3</sub>.
The active UVB wavelengths are little present in sunlight, and sufficient amounts of cholecalciferol can be produced with moderate exposure of the skin, depending on the strength of the sun.
Whether cholecalciferol and all forms of vitamin D are by definition "vitamins" can be disputed, since the definition of vitamins includes that the substance cannot be synthesized by the body and must be ingested. Cholecalciferol is synthesized by the body during UVB radiation exposure. Cholesterol is extracted from wool grease and wool wax alcohols obtained from the cleaning of wool after shearing. The cholesterol undergoes a four-step process to make 7-dehydrocholesterol, the same compound that is produced in the skin of animals. The 7-dehydrocholesterol is then irradiated with ultraviolet light. Some unwanted isomers are formed during irradiation: these are removed by various techniques, leaving a resin which melts at about room temperature and usually has a potency of 25to .
:class=skin-invert-image|500px
Cholecalciferol is also produced industrially for use in vitamin supplements from lichens, which is suitable for vegans.
Stability
Cholecalciferol is very sensitive to UV radiation and will rapidly, but reversibly, break down to form suprasterols, which can further irreversibly convert to ergosterol.
Pesticide
Rodents are somewhat more susceptible to high doses of cholecalciferol than other species, and the compound has been used in poison bait for the control of these pests. which will tend to delay time of death for several days from the time that high-dose bait is introduced. The LD<sub>50</sub> is 16.8 mg/kg, but only 9.8 mg/kg if calcium carbonate is added to the bait. Kidneys and heart are target organs. LD<sub>50</sub> of 4.4 mg/kg has been reported in rabbits, with lethality to almost all rabbits ingesting doses greater than 15 mg/kg. Toxicity has been reported across a wide range of cholecalciferol dosages, with LD<sub>50</sub> as high as 88 mg/kg or LD<sub>Lo</sub> as low as 2 mg/kg reported for dogs.
Researchers have reported that the compound is less toxic to non-target species than earlier generations of anticoagulant rodenticides (warfarin and congeners) or bromethalin, and that relay toxicosis (poisoning by eating a poisoned animal) has not been documented. Nevertheless, the same source reports that use of cholecalciferol in rodenticides may still pose a significant hazard to other animals, such as dogs and cats, when rodenticide bait or other forms of cholecalciferol are directly ingested.