Pronunciation /ˌkoʊləkælˈsɪfərɒl/ CAS Number 67-97-0 Molar mass 384.64 g/mol Density 969 kg/m³ | ATC code A11CC05 (WHO) Formula C27H44O Melting point 83 °C Boiling point 496.4 °C | |
 | ||
AHFS/Drugs.com Professional Drug Facts Pregnancy
category US: A (No risk in human studies) and C Synonyms vitamin D3, activated 7-dehydrocholesterol IUPAC ID (3β,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol | ||
Cholecalciferol, also known as vitamin D3 and colecalciferol, is a type of vitamin D found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin D deficiency including rickets. It is also used for familial hypophosphatemia, hypoparathyroidism that is causing low blood calcium, and Fanconi syndrome. It is taken by mouth.
Contents
- Vitamin D deficiency
- Other disease
- Mechanism of action
- Synthesis
- Industrial production
- Use as rodenticide
- Stability
- References
Excessive doses can result in vomiting, constipation, weakness, and confusion. Other risks include kidney stones. Normal doses are safe in pregnancy. It may not be effective in people with severe kidney disease. After being converted into 1,25-dihydroxyvitamin D, it works by increasing the uptake of calcium by the intestines. Food in which it is found include some fish, cheese, and eggs.
Cholecalciferol was first described in 1936. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Cholecalciferol is available as a generic medication and over the counter. The wholesale cost in the developing world is about 2.14 USD per 30 ml bottle. In the United States treatment costs less than 25 USD per month. Certain foods such as milk have cholecalciferol added to them in some countries.
Vitamin D deficiency
One gram is 40,000,000 (40x106) IU, equivalently 1 IU is 0.025 µg.
Recommendations vary depending on the country:
Many question whether the current recommended intake is sufficient to meet physiological needs. Individuals without regular sun exposure, the obese, and darker skinned individuals all have lower blood levels and require more supplementation.
The Institute of Medicine in 2010 recommended a maximum uptake of 4,000 IU/day, finding that the dose for lowest observed adverse effect level is 40,000 IU daily for at least 12 weeks, and that there was a single case of toxicity above 10,000 IU after more than 7 years of daily intake; this case of toxicity occurred in circumstances that have led other researchers to dispute it as a credible case to consider when making vitamin D intake recommendations. 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.
Also, there is a therapy for rickets utilizing a single dose, called stoss therapy in Europe, taking from 300,000 IU (7,500 µg) to 500,000 IU (12,500 µg = 12.5 mg), in a single dose, or in two to four divided doses.
There are conflicting reports concerning the absorption of cholecalciferol (D3) versus ergocalciferol (D2), with some studies suggesting less efficacy of D2, and others showing no difference. At present, D2 and D3 doses are frequently considered interchangeable, but more research is needed to clarify this.
Other disease
A meta-analysis of 2007 concluded that daily intake of 1000 to 2000 IU per day of vitamin D3 could reduce the incidence of colorectal cancer with minimal risk. Also a 2008 study published in Cancer Research has shown the addition of vitamin D3 (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 400 IU 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 significant 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.
Mechanism of action
It is a secosteroid, that is, a steroid molecule with one ring open. Cholecalciferol is inactive: it is converted to its active form by two hydroxylations: the first in the liver, the second in the kidney, to form calcitriol, whose action is mediated by the vitamin D receptor, a nuclear receptor which regulates the synthesis of hundreds of enzymes and is present in virtually every cell in the body.
Synthesis
It is one of the five forms of vitamin D.
7-Dehydrocholesterol is the precursor of cholecalciferol. Within the epidermal layer of skin, 7-Dehydrocholesterol undergoes an electrocyclic reaction as a result of UVB radiation, resulting in the opening of the vitamin precursor B-ring through a conrotatory pathway. Following this, the pre-cholecalciferol undergoes a [1,7] antarafacial sigmatropic rearrangement and therein finally isomerizes to form vitamin D3. It can be discussed whether cholecalciferol and all forms of vitamin D are by definition "vitamins", 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.
Cholecalciferol is then hydroxylated in the liver to become calcifediol (25-hydroxyvitamin D3). Calcifediol is then hydroxylated in the kidney, and becomes calcitriol (1,25-dihydroxyvitamin D3) or active vitamin D3.
The three steps in the synthesis of vitamin D3 are regulated as follows:
Click on icon in lower right corner to open. Click on genes, proteins and metabolites below to link to respective articles.
Industrial production
Cholecalciferol is produced industrially for use in vitamin supplements and to fortify foods. As a pharmaceutical drug it is called cholecalciferol (USAN) or colecalciferol (INN, BAN). It is produced by the ultraviolet irradiation of 7-dehydrocholesterol extracted from lanolin found in sheep's wool. 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 25,000,000 to 30,000,000 International Units per gram.
Cholecalciferol is also produced industrially for use in vitamin supplements from lichens, which is suitable for vegans.
Use as rodenticide
Rodents are somewhat more susceptible to high doses than other species, and cholecalciferol has been used in poison bait for the control of these pests. It has been claimed that the compound is less toxic to non-target species. However, in practice it has been found that use of cholecalciferol in rodenticides represents a significant hazard to other animals, such as dogs and cats. "Cholecalciferol produces hypercalcemia, which results in systemic calcification of soft tissue, leading to renal failure, cardiac abnormalities, hypertension, CNS depression, and GI upset. Signs generally develop within 18-36 hr of ingestion and can include depression, anorexia, polyuria, and polydipsia."
In New Zealand, possums have become a significant pest animal, and cholecalciferol has been used as the active ingredient in lethal gel baits and cereal pellet baits "DECAL" for possum control. The LD50 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.
Stability
Cholecalciferol is very sensitive to UV radiation and will rapidly, but reversibly, break down to form sura-sterols, which can further irreversibly convert to ergosterol.