Cholecalciferol: Difference between revisions

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{{Short description|Vitamin D3, a chemical compound}}

{{Infobox drug

| caption =  

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| pronounce = {{IPAc-en|ˌ|k|oʊ|l|ə|k|æ|l|ˈ|s|ɪ|f|ə|r|ɒ|l}}

| ATC_supplemental =  

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

| legal_AU_comment =  

| legal_status = <!--For countries not listed above-->

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| bioavailability =  

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| CAS_number = 67-97-0

| synonyms = vitamin D₃, calciol, activated 7-dehydrocholesterol

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| IUPAC_name = (3''S'',5''Z'',7''E'')-9,10-secocholesta-5,7,10(19)-trien-3-ol

}}

'''Cholecalciferol''', also known as '''vitamin D₃''' and '''colecalciferol''', is a type of [[vitamin D]] that is made by the skin when exposed to sunlight; it is found in some foods and can be taken as a [[dietary supplement]].

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Cholecalciferol is made in the skin following [[Ultraviolet#Subtypes|UVB light]] exposure. It is converted in the liver to [[calcifediol]] (25-hydroxyvitamin D) which is then converted in the kidney to [[calcitriol]] (1,25-dihydroxyvitamin D). It is found in food such as some [[fish]], beef liver, eggs, and cheese. Plants, cow milk, fruit juice, yogurt, and margarine also may have cholecalciferol added to them in some countries, including the United States.

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Cholecalciferol can be taken as an oral dietary supplement to prevent [[vitamin D deficiency]] or as a medication to treat associated diseases, including [[rickets]]. It is also used for [[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]]. Excessive doses in humans can result in vomiting, constipation, weakness, and confusion. Other risks include [[kidney stones]]. Doses greater than 40,000{{nbsp}}[[International unit|IU]] (1,000{{nbsp}}μg) per day are generally required before [[high blood calcium]] occurs. Normal doses, 800–2000 IU per day, are safe in [[pregnancy]].

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Cholecalciferol was first described in 1936. It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]]. In 2021, it was the 65th most commonly prescribed medication in the United States, with more than 10{{nbsp}}million prescriptions. Cholecalciferol is available as a [[generic medication]] and [[over the counter]].

==Medical uses==

Cholecalciferol appears to stimulate the body's [[interferon type I]] signaling system that protects against bacteria and viruses, unlike [[Vitamin D2|vitamin D₂]].

===Vitamin D deficiency===

{{Main|Vitamin D deficiency}}

*In the UK: a ‘Safe Intake’ (SI) of 8.5-10&nbsp;μg/day (30-400 IU per day) for infants < 1 year (including exclusively breastfed infants) and a SI of 10&nbsp;μg/day (400 IU per day) 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 10&nbsp;μg/day (400 IU per day).

Low levels of vitamin D 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, obese, having darker skin, or wearing clothes that cover most of the skin. Supplements are recommended for these groups of people.

The [[Institute of Medicine]] in 2010 recommended a maximum uptake of vitamin D 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.

There are conflicting reports concerning the relative effectiveness of cholecalciferol (D₃) versus [[ergocalciferol]] (D₂), with some studies suggesting less efficacy of D₂, 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 300,000 IU (7,500&nbsp;μg) to 500,000 IU (12,500&nbsp;μg = 12.5&nbsp;mg), in a single dose, or sometimes in two to four divided doses. There are concerns about the safety of such large doses.

Low circulating vitamin D levels have been associated with lower total [[testosterone]] levels in males. Vitamin D supplementation could potentially improve [[total testosterone concentration]], although more research is needed.

===Other diseases===

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 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, however, is not entirely clear 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 [[hydroxylation]]s: the first in the liver, by [[CYP2R1]] or [[CYP27A1]], to form 25-hydroxycholecalciferol ([[calcifediol]], 25-OH vitamin D₃). The second hydroxylation occurs mainly in the kidney through the action of [[CYP27B1]] to convert 25-OH vitamin D₃ into 1,25-dihydroxycholecalciferol ([[calcitriol]], 1,25-(OH)₂vitamin D₃). 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.

===Biosynthesis===

Click on icon in lower right corner to open.

{{VitaminDSynthesis_WP1531|highlight=Cholecalciferol}}

[[7-Dehydrocholesterol]] is the precursor of cholecalciferol. Within the epidermal layer of skin, 7-dehydrocholesterol undergoes an [[electrocyclic reaction]] as a result of [[Ultraviolet light#Subtypes|UVB light]] at [[wavelengths]] between 290 and 315&nbsp;nm, with peak synthesis occurring between 295 and 300&nbsp;nm. This results in the opening of the vitamin precursor B-ring through a [[Conrotatory and disrotatory|conrotatory]] pathway making [[previtamin D3|previtamin D₃]] (pre-cholecalciferol). In a process which is independent of UV light, the pre-cholecalciferol then undergoes a [1,7] antarafacial [[Sigmatropic reaction|sigmatropic]] rearrangement  and therein finally isomerizes to form vitamin D₃.

The active UVB wavelengths are present in sunlight, and sufficient amounts of cholecalciferol can be produced with moderate exposure of the skin, depending on the strength of the sun. Time of day, season, latitude, and altitude affect the strength of the sun, and pollution, cloud cover or glass all reduce the amount of UVB exposure. Exposure of face, arms and legs, averaging 5–30 minutes twice per week, may be sufficient, but the darker the skin, and the weaker the sunlight, the more minutes of exposure are needed. Vitamin D overdose is impossible from UV exposure; the skin reaches an equilibrium where the vitamin degrades as fast as it is created.

Cholecalciferol can be produced in skin from the light emitted by the UV lamps in [[tanning bed]]s, which produce ultraviolet primarily in the [[Ultraviolet light#Subtypes|UVA]] spectrum, but typically produce 4% to 10% of the total UV emissions as UVB. Levels in blood are higher in frequent users of tanning salons.

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.

The three steps in the synthesis and activation of vitamin D₃ are regulated as follows:

* Cholecalciferol is synthesized in the skin from 7-dehydrocholesterol under the action of ultraviolet B (UVB) light. It reaches an equilibrium after several minutes depending on the intensity of the UVB in the sunlight – determined by latitude, season, cloud cover, and altitude – and the age and degree of pigmentation of the skin.

* Hydroxylation in the kidneys of calcifediol to calcitriol by [[25-Hydroxyvitamin D3 1-alpha-hydroxylase|1-alpha-hydroxylase]] is tightly regulated: it is stimulated by [[parathyroid hormone]] and serves as the major control point in the production of the active circulating hormone [[calcitriol]] (1,25-dihydroxyvitamin D₃).

==Industrial production==

Cholecalciferol is produced industrially for use in [[multivitamin|vitamin supplement]]s and [[food fortification|to fortify foods]]. As a [[pharmaceutical drug]] it is called cholecalciferol ([[United States Adopted Name|USAN]]) or colecalciferol ([[International Nonproprietary Name|INN]], [[British Approved Name|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.

[[File:Cholecalciferol synth.png|500px]]

Cholecalciferol is also produced industrially for use in vitamin supplements from [[lichen]]s, which is suitable for vegans.

==Stability==

Cholecalciferol is very sensitive to [[ultraviolet|UV radiation]] and will rapidly, but reversibly, break down to form supra-sterols, which can further irreversibly convert to [[ergosterol]].

==Pesticide==

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.

The mechanism of high dose cholecalciferol is that it can produce "[[hypercalcemia]], which results in systemic calcification of soft tissue, leading to [[kidney failure]], [[cardiac]] abnormalities, [[hypertension]], CNS depression, and GI upset. Signs generally develop within 18-36 hr of ingestion and can include depression, [[loss of appetite]], [[polyuria]], and [[polydipsia]]." High-dose cholecalciferol will tend to rapidly accumulate in [[adipose]] tissue yet release more slowly which will tend to delay time of death for several days from the time that high-dose bait is introduced.

   

In New Zealand, [[Common brushtail possum|possums]] have become a significant pest animal. For possum control, cholecalciferol has been used as the active ingredient in lethal baits. The [[Median lethal dose|LD₅₀]] is 16.8&nbsp;mg/kg, but only 9.8&nbsp;mg/kg if calcium carbonate is added to the bait. Kidneys and heart are target organs. LD₅₀ of 4.4&nbsp;mg/kg has been reported in rabbits, with lethality to almost all rabbits ingesting doses greater than 15&nbsp;mg/kg. Toxicity has been reported across a wide range of cholecalciferol dosages, with LD₅₀ as high as 88&nbsp;mg/kg or LD_Lo as low as 2&nbsp;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 [[Congener (chemistry)|congeners]]) or [[Bromethalin]], and that [[Relay toxicity|relay toxicosis]] (poisoning by eating a poisoned animal) has not been documented. Nevertheless, the same source reports that use of cholecalciferol in [[rodenticide]]s 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.

== See also ==

* [[Hypervitaminosis D]], Vitamin D poisoning

* [[25-Hydroxyvitamin D 1-alpha-hydroxylase]], a kidney [[enzyme]] that converts calcifediol to calcitriol

== External links ==

* [https://webbook.nist.gov/cgi/cbook.cgi?ID=C67970 NIST Chemistry WebBook page for cholecalciferol]

* [https://rep.bioscientifica.com/view/journals/rep/144/2/135.xml Vitamin D metabolism, sex hormones, and male reproductive function.]

{{Vitamins}}

{{Sterols}}

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{{二次利用|date=25 March 2024}}

[[Category:Cyclopentanes]]