Cholecalciferol

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Cholecalciferol, also known as vitamin D₃ or colecalciferol, is a type of vitamin D that is produced by the skin when exposed to UVB light; it is found in certain foods and can be taken as a dietary supplement.<ref>Template:Cite book</ref>

Cholecalciferol is synthesised in the skin following sunlight exposure.<ref name="Norman">Template:Cite journal</ref> 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).<ref name="Norman"/> One of calcitriol's most important functions is to promote calcium uptake by the intestines.<ref name=PPA2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Cholecalciferol is present in food such as fatty fish, beef liver, eggs, and cheese.<ref name=NIH2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=IMFNBDRICD2010>Template:Cite book</ref> In some countries, cholecalciferol is also added to products like plants, cow milk, fruit juice, yogurt, and margarine.<ref name=NIH2016/><ref name=IMFNBDRICD2010/>

Cholecalciferol can be taken orally as a dietary supplement to prevent vitamin D deficiency or as a medication to treat associated diseases, including rickets.<ref name=BNF69>Template:Cite book</ref><ref name=WHO2008>Template:Cite book</ref> It is also used in the management of familial hypophosphatemia, hypoparathyroidism that is causing low blood calcium, and Fanconi syndrome.<ref name=WHO2008/><ref name=Ric2015>Template:Cite book</ref> Vitamin-D supplements may not be effective in people with severe kidney disease.<ref name=UK2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Ric2015/> Excessive doses in humans can result in vomiting, constipation, muscle weakness, and confusion.<ref name=PPA2016/> Other risks include kidney stones.<ref name=UK2016/> Doses greater than Template:ValTemplate:NbspIU (Template:Val) per day are generally required before high blood calcium occurs.<ref name="Vieth">Template:Cite journal</ref> Normal doses, Template:Val IU per day, are safe in pregnancy.<ref name=PPA2016/>

Cholecalciferol was first described in 1936.<ref name=Fis2006>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> In 2022, it was the 62nd most commonly prescribed medication in the United States, with more than 10Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Cholecalciferol is available as a generic medication.<ref name=Ric2015/><ref name=merckvet2014/><ref name=usda2006>Template:Cite conference</ref>

Medical uses

Cholecalciferol (vitamin D₃) appears to stimulate the body's interferon type I signaling system that protects against bacteria and viruses, unlike vitamin D₂.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Vitamin D deficiency

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.<ref name=Norman/> As a medication, cholecalciferol may be taken as a dietary supplement to prevent or to treat vitamin D deficiency. One gram is Template:Val (Template:Val) IU, equivalently Template:Val is Template:Val, or Template:Val. Dietary reference intake values for vitamin D (ergocalciferol, which is D₂, or cholecalciferol, which is D₃), or both, have been established and recommendations vary depending on the country:

• In the US: Template:Val (Template:Val) for all individuals (males, females, pregnant/lactating women) between the ages of 1 and 70 years, inclusive. For all individuals older than 70 years, Template:Val (Template:Val) is recommended.<ref name="Institute of Medicine">DRIs for Calcium and Vitamin D Template:Webarchive</ref>
• In the EU: Template:Val (Template:Val) for all people older than 1 year and Template:Val (Template:Val) for infants aged 7–11 months, assuming minimal cutaneous vitamin D synthesis.<ref name="European Food Safety Agency">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• In the UK: a 'Safe Intake' (SI) of Template:Val (Template:Val) for infants < 1 year (including exclusively breastfed infants) and an SI of Template:Val (Template:Val) 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 Template:Val (Template:Val).<ref name="Scientif Advisory Commitee on Nutrition">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Low levels of vitamin D₃ 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.<ref name="pmid19543765">Template:Cite journal</ref><ref name = "NHSVD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Supplements are recommended for these groups of people.<ref name = "NHSVD" />

The Institute of Medicine in 2010 recommended a maximum uptake of vitamin D of Template:Val, finding that the dose for lowest observed adverse effect level is 40,000 IU daily for at least 12 weeks,<ref name="pmid10232622"/> and that there was a single case of toxicity above Template:Val after more than seven years of daily intake; this case of toxicity occurred in circumstances that have led other researchers to dispute whether it is a credible case to consider when making vitamin D intake recommendations.<ref name="pmid10232622">Template:Cite journal</ref> 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.<ref name="pmid20139241">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

A much less common use of cholecalciferol therapy in rickets utilizes a single large dose and has been called stoss therapy.<ref name="pmid8071764">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid26913455">Template:Cite journal</ref> Treatment is given either orally or by intramuscular injection of Template:Val (Template:Val) to Template:Val (Template:Val = Template:Val), in a single dose, or sometimes in two to four divided doses. There are concerns about the safety of such large doses.<ref name="pmid26913455"/>

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.<ref>Template:Cite journal</ref>

Other diseases

A meta-analysis of 2007 concluded that daily intake of Template:Val of vitamin D₃ could reduce the incidence of colorectal cancer with minimal risk.<ref name="pmid17296473">Template:Cite journal</ref> 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.<ref name="pmid18829535">Template:Cite journal</ref> In humans, with Template:Val daily, there was no effect of cholecalciferol supplements on the risk of colorectal cancer.<ref name="pmid16481636">Template:Cite journal</ref>

Supplements are not recommended for prevention of cancer as any effects of cholecalciferol are very small.<ref>Template:Cite journal</ref> Although correlations exist between low levels of blood serum cholecalciferol and higher rates of various cancers, multiple sclerosis, tuberculosis, heart disease, and diabetes,<ref name="PMC1470481">Template:Cite journal</ref> the consensus is that supplementing levels is not beneficial.<ref name="Ross_2011">Template:Cite journal</ref> It is thought that tuberculosis may result in lower levels.<ref>Template:Cite journal</ref> It, however, is not entirely clear how the two are related.<ref>Template:Cite journal</ref>

Biochemistry

Structure

Cholecalciferol is one of the five forms of vitamin D.<ref>Template:DorlandsDict</ref> Cholecalciferol is a secosteroid, that is, a steroid molecule with one ring open.<ref name="River">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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 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.<ref name=Norman/>

Biosynthesis

Click on icon in lower right corner to open. Template:VitaminDSynthesis WP1531

7-Dehydrocholesterol is the precursor of cholecalciferol.<ref name=Norman/> Within the epidermal layer of skin, 7-dehydrocholesterol undergoes an electrocyclic reaction as a result of UVB light at wavelengths between Template:Val, with peak synthesis occurring at Template:Val.<ref name="WackerHolick2013">Template:Cite journal</ref> This results in the opening of the vitamin precursor B-ring through a conrotatory pathway making previtamin D₃ (pre-cholecalciferol).<ref>Template:Cite journal</ref> In a process which is independent of UV light, the pre-cholecalciferol then undergoes a [1,7] antarafacial sigmatropic rearrangement<ref>Template:Cite journal</ref> and therein finally isomerizes to form vitamin D₃.

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.<ref name="WackerHolick2013"/> 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 Template:Val 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.<ref name="WackerHolick2013"/>

Cholecalciferol can be produced in skin from the light emitted by the UV lamps in tanning beds, which produce ultraviolet primarily in the 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.<ref name="WackerHolick2013"/>

A 293 nanometer UVB light emitting diode (LED) was found to be 2.4 times more efficient in producing vitamin D₃ than the sun in less than Template:Frac the time. (https://pubmed.ncbi.nlm.nih.gov/28904394/).

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.<ref name=Norman/>

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 endoplasmic reticulum of liver hepatocytes of cholecalciferol to calcifediol (25-hydroxycholecalciferol) by 25-hydroxylase is loosely regulated, if at all, and blood levels of this molecule largely reflect the amount of cholecalciferol produced in the skin combined with any vitamin D₂ or D₃ ingested.
• Hydroxylation in the kidneys of calcifediol to calcitriol by 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).<ref name=Norman/>

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.<ref name="AGD Nutrition">Vitamin D3 Story. Template:Webarchive Retrieved 8 April 2012.</ref> 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 Template:Val.

File:Cholecalciferol synth.png

Cholecalciferol is also produced industrially for use in vitamin supplements from lichens, which is suitable for vegans.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Wang">Template:Cite journal</ref>

Stability

Cholecalciferol is very sensitive to UV radiation and will rapidly, but reversibly, break down to form supra-sterols, which can further irreversibly convert to ergosterol.Template:Citation needed

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.<ref name=vertebratePestProceedings1984>Template:Cite conference</ref><ref name=usda2006/>

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 Template:Val of ingestion and can include depression, loss of appetite, polyuria, and polydipsia."<ref name=merckvet2014/> High-dose cholecalciferol will tend to rapidly accumulate in adipose tissue yet release more slowly<ref name=bjn20070309>Template:Cite journal</ref> which will tend to delay time of death for several days from the time that high-dose bait is introduced.<ref name=vertebratePestProceedings1984/>

In New Zealand, possums have become a significant pest animal. For possum control, cholecalciferol has been used as the active ingredient in lethal baits.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The LD₅₀ is 16.8 mg/kg, but only 9.8 mg/kg if calcium carbonate is added to the bait.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Kidneys and heart are target organs.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> LD₅₀ of 4.4 mg/kg has been reported in rabbits, with lethality to almost all rabbits ingesting doses greater than 15 mg/kg.<ref name=henderson2000>R. J. Henderson and C. T. Eason (2000), Acute toxicity of cholecalciferol and gliftor baits to the European rabbit, Oryctolagus cuniculus, Wildlife Research 27(3) 297-300.</ref> Toxicity has been reported across a wide range of cholecalciferol dosages, with LD₅₀ as high as 88 mg/kg or LD_Lo as low as 2 mg/kg reported for dogs.<ref name=peterson2013>Michael E.Peterson & Kerstin Fluegeman, Cholecalciferol (Topic Review), Topics in Companion Animal Medicine, Volume 28, Issue 1, February 2013, Pages 24-27.</ref>

Researchers have reported that the compound is less toxic to non-target species than earlier generations of anticoagulant rodenticides (Warfarin and congeners) or Bromethalin,<ref name=kocher2010>Template:Cite journal</ref> and that relay toxicosis (poisoning by eating a poisoned animal) has not been documented.<ref name=merckvet2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=merckvet2014/>

See also

• Hypervitaminosis D, vitamin D poisoning
• Ergocalciferol, vitamin D₂
• 25-Hydroxyvitamin D 1-alpha-hydroxylase, a kidney enzyme that converts calcifediol to calcitriol

External links

• Ultraviolet B Light Emitting Diodes (LEDs) Are More Efficient and Effective in Producing Vitamin D3 in Human Skin Compared to Natural Sunlight
• NIST Chemistry WebBook page for cholecalciferol
• Vitamin D metabolism, sex hormones, and male reproductive function.