View source for Chemistry:Cholecalciferol

{{Short description|Vitamin D3, a chemical compound}}
{{Infobox drug
| INN = Colecalciferol
| image = Cholecalciferol.svg 
| width = 
| alt = 
| image2 = Cholecalciferol-vitamin-D3-from-xtal-3D-sticks.png
| width2 = 
| alt2 = 
| caption = 

<!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|k|oʊ|l|ə|k|æ|l|ˈ|s|ɪ|f|ə|r|ɒ|l}}
| tradename = 
| Drugs.com = {{Drugs.com|ppa|cholecalciferol}}
| MedlinePlus = 
| DailyMedID = Cholecalciferol
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment = 
| pregnancy_category= 
| routes_of_administration = By mouth, [[Biology:Intramuscular injection|intramuscular]]
| class = 
| ATC_prefix = A11
| ATC_suffix = CC05
| ATC_supplemental = 

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment = 
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment = 
| legal_US = OTC
| legal_US_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->
| bioavailability = 
| protein_bound = 
| metabolism = 
| metabolites =
| onset = 
| elimination_half-life = 
| duration_of_action =
| excretion =

<!-- Identifiers -->
| CAS_number = 67-97-0
| CAS_supplemental = 
| PubChem = 5280795
| PubChemSubstance = 
| IUPHAR_ligand = 
| DrugBank = DB00169
| ChemSpiderID = 4444353
| UNII = 1C6V77QF41
| KEGG = C05443
| ChEBI = 28940
| ChEMBL = 1042
| NIAID_ChemDB =
| synonyms = vitamin D<sub>3</sub>, calciol, activated 7-dehydrocholesterol

<!-- Chemical and physical data --> 
| IUPAC_name = (3''S'',5''Z'',7''E'')-9,10-secocholesta-5,7,10(19)-trien-3-ol
| C=27|H=44|O=1
| SMILES = O[C@@H]1CC(\C(=C)CC1)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CCCC(C)C)C
| StdInChI = 1S/C27H44O/c1-19(2)8-6-9-21(4)25-15-16-26-22(10-7-17-27(25,26)5)12-13-23-18-24(28)14-11-20(23)3/h12-13,19,21,24-26,28H,3,6-11,14-18H2,1-2,4-5H3/b22-12+,23-13-/t21-,24+,25-,26+,27-/m1/s1
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = QYSXJUFSXHHAJI-YRZJJWOYSA-N
| density = 
| density_notes = 
| melting_point = 83 to 86
| melting_high = 
| melting_notes = 
| boiling_point = 496.4
| boiling_notes = 
| solubility = Practically insoluble in water, freely soluble in ethanol, methanol and some other organic solvents. Slightly soluble in vegetable oils.
| sol_units =
| specific_rotation = 
}}

'''Cholecalciferol''', also known as '''vitamin D<sub>3</sub>''' and '''colecalciferol''', is a type of [[Chemistry:Vitamin D|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.<ref>{{cite book | vauthors = Coulston AM, Boushey C, Ferruzzi M |title=Nutrition in the Prevention and Treatment of Disease |date=2013 |publisher=Academic Press |isbn=9780123918840 |page=818 |url=https://books.google.com/books?id=pmapb3rvzpYC&pg=PA818 |access-date=29 December 2016 |archive-url=https://web.archive.org/web/20161230000458/https://books.google.ca/books?id=pmapb3rvzpYC&pg=PA818 |archive-date=30 December 2016 |url-status=live }}</ref>

<!-- Sources and mechanism -->
Cholecalciferol is made in the skin following [[Physics:Ultraviolet#Subtypes|UVB light]] exposure.<ref name="Norman">{{cite journal | vauthors = Norman AW | title = From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health | journal = The American Journal of Clinical Nutrition | volume = 88 | issue = 2 | pages = 491S–499S | date = August 2008 | pmid = 18689389 | doi = 10.1093/ajcn/88.2.491S | doi-access = free }}</ref> It is converted in the liver to [[Chemistry:Calcifediol|calcifediol]] (25-hydroxyvitamin D) which is then converted in the kidney to [[Chemistry:Calcitriol|calcitriol]] (1,25-dihydroxyvitamin D).<ref name="Norman"/> One of its actions is to increase [[Chemistry:Calcium|calcium]] uptake by the intestines.<ref name=PPA2016>{{cite web|title=Cholecalciferol (Professional Patient Advice) - Drugs.com|url=https://www.drugs.com/ppa/cholecalciferol.html|website=www.drugs.com|access-date=29 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161230002705/https://www.drugs.com/ppa/cholecalciferol.html|archive-date=30 December 2016}}</ref> It is found in food such as some [[Biology:Fish|fish]], beef liver, eggs, and cheese.<ref name=NIH2016>{{cite web|title=Office of Dietary Supplements - Vitamin D|url=https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/|website=ods.od.nih.gov|access-date=30 December 2016|date=11 February 2016|url-status=live|archive-url=https://web.archive.org/web/20161231073744/https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/|archive-date=31 December 2016}}</ref><ref name=IMFNBDRICD2010>{{cite book | collaboration = Institute of Medicine (US); Committee to Review Dietary Reference Intakes for Vitamin D and Calcium | vauthors = Ross AC, Taylor CL, Yaktine AL, Del Valle HB |title=Dietary Reference Intakes for Calcium and Vitamin D |date=2011 | publisher = National Academies Press |doi=10.17226/13050 |pmid=21796828 |isbn=978-0-309-16394-1 | s2cid = 58721779 |url=https://www.ncbi.nlm.nih.gov/books/NBK56070/pdf/Bookshelf_NBK56070.pdf}}</ref> Plants, cow milk, fruit juice, yogurt, and margarine also may have cholecalciferol added to them in some countries, including the United States.<ref name=NIH2016/><ref name=IMFNBDRICD2010/>

<!-- Use as a medication -->
Cholecalciferol can be taken as an oral dietary supplement to prevent [[Medicine:Vitamin D deficiency|vitamin D deficiency]] or as a medication to treat associated diseases, including [[Medicine:Rickets|rickets]].<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|pages=703–704|edition=69}}</ref><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 |  publisher = World Health Organization }}</ref> It is also used for familial hypophosphatemia, [[Medicine:Hypoparathyroidism|hypoparathyroidism]] that is causing low blood calcium, and [[Medicine:Fanconi syndrome|Fanconi syndrome]].<ref name=WHO2008/><ref name=Ric2015>{{cite book| vauthors = Hamilton R |title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=231}}</ref> Vitamin-D supplements may not be effective in people with severe [[Medicine:Kidney disease|kidney disease]].<ref name=UK2016>{{cite web|title=Aviticol 1 000 IU Capsules - Summary of Product Characteristics (SPC) - (eMC)|url=https://www.medicines.org.uk/emc/medicine/31838|website=www.medicines.org.uk|access-date=29 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161230085711/https://www.medicines.org.uk/emc/medicine/31838|archive-date=30 December 2016}}</ref><ref name=Ric2015/> Excessive doses in humans can result in vomiting, constipation, weakness, and confusion.<ref name=PPA2016/> Other risks include kidney stones.<ref name=UK2016/> Doses greater than 40,000{{nbsp}}[[International unit|IU]] (1,000{{nbsp}}μg) per day are generally required before high blood calcium occurs.<ref name="Vieth">{{cite journal |vauthors=Vieth R |title=Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety |journal=The American Journal of Clinical Nutrition |volume=69 |issue=5 |pages=842–56 |date=May 1999 |pmid=10232622 |url=http://www.ajcn.org/content/69/5/842.full.pdf |doi=10.1093/ajcn/69.5.842|doi-access=free }}</ref> Normal doses, 800–2000 IU per day, are safe in [[Medicine:Pregnancy|pregnancy]].<ref name=PPA2016/>

<!-- History and culture -->
Cholecalciferol was first described in 1936.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=451 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA451|language=en|access-date=29 December 2016|archive-url=https://web.archive.org/web/20161230085612/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA451|archive-date=30 December 2016|url-status=live}}</ref> It is on the [[Medicine:WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 |  publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2021, it was the 65th most commonly prescribed medication in the United States, with more than 10{{nbsp}}million prescriptions.<ref>{{cite web | title = The Top 300 of 2021 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 14 January 2024}}</ref><ref>{{cite web | title = Cholecalciferol - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Cholecalciferol | access-date = 14 January 2024}}</ref> Cholecalciferol is available as a generic medication and over the counter.<ref name=Ric2015/><ref name=merckvet2014/><ref name=usda2006>{{cite conference | vauthors = Rizor SE, Arjo WM, Bulkin S, Nolte DL |title=Efficacy of Cholecalciferol Baits for Pocket Gopher Control and Possible Effects on Non-Target Rodents in Pacific Northwest Forests |url=https://naldc.nal.usda.gov/download/39036/PDF |conference=Vertebrate Pest Conference (2006) |publisher=USDA |quote=0.15% cholecalciferol bait appears to have application for pocket gopher control.' Cholecalciferol can be a single high-dose toxicant or a cumulative multiple low-dose toxicant. |access-date=27 August 2019 |archive-url=https://web.archive.org/web/20120914083512/http://naldc.nal.usda.gov/download/39036/PDF |archive-date=14 September 2012 |url-status=live }}</ref>

==Medical uses==
Cholecalciferol appears to stimulate the body's [[Biology:Interferon type I|interferon type I]] signaling system that protects against bacteria and viruses, unlike vitamin D<sub>2</sub>.<ref>{{Cite web | vauthors = Haridy R |date= 28 February 2022 |title=One type of vitamin D found to boost immune system, another may hinder it |url=https://newatlas.com/health-wellbeing/differences-between-vitamin-d2-d3-immune-system-supplements/ |access-date=7 April 2022 |website=New Atlas |language=en-US}}</ref>

===Vitamin D deficiency===
{{Main|Medicine: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 [[Chemistry:Calcitriol|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 40,000,000 (40x10<sup>6</sup>) [[International unit|IU]], equivalently 1 IU is 0.025&nbsp;μg or 25 ng. Dietary reference intake values for vitamin D (cholecalciferol and/or ergocalciferol) have been established and recommendations vary depending on the country: 
*In the US: 15&nbsp;μg/d (600 IU per day) for all individuals (males, females, pregnant/lactating women) between the ages of 1 and 70 years old, inclusive. For all individuals older than 70 years, 20&nbsp;μg/d (800 IU per day) is recommended.<ref name="Institute of Medicine">[http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/DRI-Values.aspx DRIs for Calcium and Vitamin D] {{webarchive|url=https://web.archive.org/web/20101224064915/http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/DRI-Values.aspx |date=24 December 2010 }}</ref>
*In the EU (except France): 20&nbsp;μg/d (800 IU per day)
*In France: 25&nbsp;μg/d (1000 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.<ref name="pmid19543765">{{cite journal | vauthors = Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J | title = Global vitamin D status and determinants of hypovitaminosis D | journal = Osteoporos Int | volume = 20 | issue = 11 | pages = 1807–20 | date = November 2009 | pmid = 19543765 | doi = 10.1007/s00198-009-0954-6 | s2cid = 52858668 | url = https://research.vumc.nl/en/publications/4861a0b5-49a4-47e2-bbb4-dda46208c058}}</ref><ref name = "NHSVD">{{cite web |url=http://www.nhs.uk/Conditions/vitamins-minerals/Pages/Vitamin-D.aspx |title=Vitamins and minerals – Vitamin D |website=National Health Service |date=3 August 2020 |access-date=15 November 2020}}</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 4,000 IU/day, 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 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.<ref name="pmid10232622">{{cite journal | vauthors = Vieth R | title = Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety | journal = The American Journal of Clinical Nutrition | volume = 69 | issue = 5 | pages = 842–56 | date = May 1999 | pmid = 10232622 | doi = 10.1093/ajcn/69.5.842 | doi-access = free }}</ref> Patients with severe vitamin D deficiency will require treatment with a [[Medicine:Loading dose|loading dose]]; its magnitude can be calculated based on the actual serum 25-hydroxy-vitamin D level and body weight.<ref name="pmid20139241">{{cite journal | vauthors = van Groningen L, Opdenoordt S, van Sorge A, Telting D, Giesen A, de Boer H | title = Cholecalciferol loading dose guideline for vitamin D-deficient adults | journal = European Journal of Endocrinology | volume = 162 | issue = 4 | pages = 805–11 | date = April 2010 | pmid = 20139241 | doi = 10.1530/EJE-09-0932 | doi-access = free }}</ref>

There are conflicting reports concerning the relative effectiveness of cholecalciferol (D<sub>3</sub>) versus [[Chemistry:Ergocalciferol|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.<ref>{{cite journal | vauthors = Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S | display-authors = 6 | title = Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis | journal = The American Journal of Clinical Nutrition | volume = 95 | issue = 6 | pages = 1357–64 | date = June 2012 | pmid = 22552031 | pmc = 3349454 | doi = 10.3945/ajcn.111.031070 }}</ref>

A much less common use of cholecalciferol therapy in [[Medicine:Rickets|rickets]] utilizes a single large dose and has been called ''stoss'' therapy.<ref name="pmid8071764">{{cite journal | vauthors = Shah BR, Finberg L | title = Single-day therapy for nutritional vitamin D-deficiency rickets: a preferred method | journal = The Journal of Pediatrics | volume = 125 | issue = 3 | pages = 487–90 | date = September 1994 | pmid = 8071764 | doi = 10.1016/S0022-3476(05)83303-7 }}</ref><ref>{{cite journal | vauthors = Chatterjee D, Swamy MK, Gupta V, Sharma V, Sharma A, Chatterjee K | title = Safety and Efficacy of Stosstherapy in Nutritional Rickets | journal = Journal of Clinical Research in Pediatric Endocrinology | volume = 9 | issue = 1 | pages = 63–69 | date = March 2017 | pmid = 27550890 | pmc = 5363167 | doi = 10.4274/jcrpe.3557 }}</ref><ref name="pmid26913455">{{cite journal | vauthors = Bothra M, Gupta N, Jain V | title = Effect of intramuscular cholecalciferol megadose in children with nutritional rickets | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 29 | issue = 6 | pages = 687–92 | date = June 2016 | pmid = 26913455 | doi = 10.1515/jpem-2015-0031 | s2cid = 40611968 }}</ref> Treatment is given either orally or by [[Biology:Intramuscular injection|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.<ref name="pmid26913455"/>

Low circulating vitamin D levels have been associated with lower total [[Chemistry:Testosterone|testosterone]] levels in males. Vitamin D supplementation could potentially improve total testosterone concentration, although more research is needed.<ref>{{cite journal | vauthors = Chen C, Zhai H, Cheng J, Weng P, Chen Y, Li Q, Wang C, Xia F, Wang N, Lu Y | display-authors = 6 | title = Causal Link Between Vitamin D and Total Testosterone in Men: A Mendelian Randomization Analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 8 | pages = 3148–3156 | date = August 2019 | pmid = 30896763 | doi = 10.1210/jc.2018-01874 | s2cid = 84841517 | doi-access = free }}</ref>

===Other diseases===
A meta-analysis of 2007 concluded that daily intake of 1000 to 2000 IU per day of vitamin D<sub>3</sub> could reduce the incidence of colorectal cancer with minimal risk.<ref name="pmid17296473">{{cite journal | vauthors = Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, Newmark HL, Giovannucci E, Wei M, Holick MF | display-authors = 6 | title = Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis | journal = American Journal of Preventive Medicine | volume = 32 | issue = 3 | pages = 210–6 | date = March 2007 | pmid = 17296473 | doi = 10.1016/j.amepre.2006.11.004 | type = Meta-Analysis }}</ref> 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.<ref name="pmid18829535">{{cite journal | vauthors = Yang K, Kurihara N, Fan K, Newmark H, Rigas B, Bancroft L, Corner G, Livote E, Lesser M, Edelmann W, Velcich A, Lipkin M, Augenlicht L | display-authors = 6 | title = Dietary induction of colonic tumors in a mouse model of sporadic colon cancer | journal = Cancer Research | volume = 68 | issue = 19 | pages = 7803–10 | date = October 2008 | pmid = 18829535 | doi = 10.1158/0008-5472.CAN-08-1209 | doi-access = free }}</ref> In humans, with 400 IU daily, there was no effect of cholecalciferol supplements on the risk of colorectal cancer.<ref name="pmid16481636">{{cite journal | vauthors = Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, Margolis KL, Ockene JK, Phillips L, Pottern L, Prentice RL, Robbins J, Rohan TE, Sarto GE, Sharma S, Stefanick ML, Van Horn L, Wallace RB, Whitlock E, Bassford T, Beresford SA, Black HR, Bonds DE, Brzyski RG, Caan B, Chlebowski RT, Cochrane B, Garland C, Gass M, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Jackson RD, Johnson KC, Judd H, Kooperberg CL, Kuller LH, LaCroix AZ, Lane DS, Langer RD, Lasser NL, Lewis CE, Limacher MC, Manson JE | display-authors = 6 | title = Calcium plus vitamin D supplementation and the risk of colorectal cancer | journal = The New England Journal of Medicine | volume = 354 | issue = 7 | pages = 684–96 | date = February 2006 | pmid = 16481636 | doi = 10.1056/NEJMoa055222 | s2cid = 20826870 | url = http://www.escholarship.org/uc/item/43r416nc | doi-access = free }}</ref>

Supplements are not recommended for prevention of cancer as any effects of cholecalciferol are very small.<ref>{{cite journal | vauthors = Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C | display-authors = 6 | title = Vitamin D supplementation for prevention of mortality in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD007470 | date = January 2014 | pmid = 24414552 | doi = 10.1002/14651858.cd007470.pub3 }}</ref> Although correlations exist between low levels of blood serum cholecalciferol and higher rates of various cancers, multiple sclerosis, [[Medicine:Tuberculosis|tuberculosis]], heart disease, and diabetes,<ref name="PMC1470481">{{cite journal | vauthors = Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF | title = The role of vitamin D in cancer prevention | journal = American Journal of Public Health | volume = 96 | issue = 2 | pages = 252–61 | date = February 2006 | pmid = 16380576 | pmc = 1470481 | doi = 10.2105/AJPH.2004.045260 }}</ref> the consensus is that supplementing levels is not beneficial.<ref name="Ross_2011">{{cite journal | vauthors = Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA | display-authors = 6 | title = The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 1 | pages = 53–8 | date = January 2011 | pmid = 21118827 | pmc = 3046611 | doi = 10.1210/jc.2010-2704 | doi-access = free }}</ref> It is thought that tuberculosis may result in lower levels.<ref>{{cite journal | vauthors = Gou X, Pan L, Tang F, Gao H, Xiao D | title = The association between vitamin D status and tuberculosis in children: A meta-analysis | journal = Medicine | volume = 97 | issue = 35 | pages = e12179 | date = August 2018 | pmid = 30170465 | pmc = 6392646 | doi = 10.1097/MD.0000000000012179 }}</ref> It, however, is not entirely clear how the two are related.<ref>{{cite journal | vauthors = Keflie TS, Nölle N, Lambert C, Nohr D, Biesalski HK | title = Vitamin D deficiencies among tuberculosis patients in Africa: A systematic review | journal = Nutrition | volume = 31 | issue = 10 | pages = 1204–12 | date = October 2015 | pmid = 26333888 | doi = 10.1016/j.nut.2015.05.003 }}</ref>

==Biochemistry==
=== Structure ===
Cholecalciferol is one of the five forms of [[Chemistry:Vitamin D|vitamin D]].<ref>{{DorlandsDict|two/000020436|cholecalciferol}}</ref> Cholecalciferol is a [[Chemistry:Secosteroid|secosteroid]], that is, a steroid molecule with one ring open.<ref name="River">{{cite web |url=http://vitamind.ucr.edu/about/ |title=About Vitamin D |publisher=University of California, Riverside |date=November 2011 |access-date=15 October 2017 |url-status=live |archive-url=https://web.archive.org/web/20171016014311/http://vitamind.ucr.edu/about/ |archive-date=16 October 2017 }}</ref>

===Mechanism of action===
By itself cholecalciferol is inactive. It is converted to its active form by two [[Biology:Hydroxylation|hydroxylation]]s: the first in the liver, by [[Biology:CYP2R1|CYP2R1]] or [[Biology:CYP27A1|CYP27A1]], to form 25-hydroxycholecalciferol ([[Chemistry:Calcifediol|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 ([[Chemistry:Calcitriol|calcitriol]], 1,25-(OH)<sub>2</sub>vitamin D<sub>3</sub>). All these metabolites are bound in blood to the [[Chemistry:Vitamin D-binding protein|vitamin D-binding protein]]. The action of calcitriol is mediated by the [[Biology:Vitamin D receptor|vitamin D receptor]], a [[Biology:Nuclear receptor|nuclear receptor]] which regulates the synthesis of hundreds of proteins and is present in virtually every cell in the body.<ref name=Norman/>

===Biosynthesis===
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[[Chemistry:7-Dehydrocholesterol|7-Dehydrocholesterol]] is the precursor of cholecalciferol.<ref name=Norman/> Within the epidermal layer of skin, 7-dehydrocholesterol undergoes an [[Chemistry:Electrocyclic reaction|electrocyclic reaction]] as a result of UVB light at wavelengths between 290 and 315&nbsp;nm, with peak synthesis occurring between 295 and 300&nbsp;nm.<ref name="WackerHolick2013">{{cite journal | vauthors = Wacker M, Holick MF | title = Sunlight and Vitamin D: A global perspective for health | journal = Dermato-Endocrinology | volume = 5 | issue = 1 | pages = 51–108 | date = January 2013 | pmid = 24494042 | pmc = 3897598 | doi = 10.4161/derm.24494 }}</ref> This results in the opening of the vitamin precursor B-ring through a [[Chemistry:Conrotatory and disrotatory|conrotatory]] pathway making [[Chemistry:Previtamin D3|previtamin D<sub>3</sub>]] (pre-cholecalciferol).<ref>{{cite journal | vauthors = MacLaughlin JA, Anderson RR, Holick MF | s2cid = 23011680 | title = Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin | journal = Science | volume = 216 | issue = 4549 | pages = 1001–3 | date = May 1982 | pmid = 6281884 | doi = 10.1126/science.6281884 | bibcode = 1982Sci...216.1001M }}</ref> In a process which is independent of UV light, the pre-cholecalciferol then undergoes a [1,7] antarafacial [[Chemistry:Sigmatropic reaction|sigmatropic]] rearrangement <ref>{{cite journal | vauthors = Okamura WH, Elnagar HY, Ruther M, Dobreff S | title = Thermal [1,7]-sigmatropic shift of previtamin D<sub>3</sub> to vitamin D<sub>3</sub>: synthesis and study of pentadeuterio derivatives | journal = Journal of Organic Chemistry | volume = 58 | pages = 600–610 | year = 1993 | doi = 10.1021/jo00055a011 | issue = 3 }}</ref> and therein finally isomerizes to form vitamin D<sub>3</sub>.

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.<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 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.<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"/>

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 D<sub>3</sub> 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 [[Biology:Hepatocyte|hepatocyte]]s of cholecalciferol to calcifediol (25-hydroxycholecalciferol) by [[Biology:CYP2R1|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 D<sub>2</sub> or D<sub>3</sub> ingested.
* Hydroxylation in the kidneys of calcifediol to calcitriol by [[Biology:25-Hydroxyvitamin D3 1-alpha-hydroxylase|1-alpha-hydroxylase]] is tightly regulated: it is stimulated by [[Biology:Parathyroid hormone|parathyroid hormone]] and serves as the major control point in the production of the active circulating hormone [[Chemistry:Calcitriol|calcitriol]] (1,25-dihydroxyvitamin D<sub>3</sub>).<ref name=Norman/>

==Industrial production==
Cholecalciferol is produced industrially for use in [[Chemistry:Multivitamin|vitamin supplement]]s and [[Chemistry:Food fortification|to fortify foods]]. As a pharmaceutical drug it is called cholecalciferol (USAN) or colecalciferol (INN, [[Chemistry:British Approved Name|BAN]]). It is produced by the [[Physics:Ultraviolet|ultraviolet]] irradiation of 7-dehydrocholesterol extracted from [[Chemistry:Lanolin|lanolin]] found in sheep's wool.<ref name="AGD Nutrition">[http://www.agdnutrition.com/d3-story.html Vitamin D3 Story.] {{webarchive|url=https://web.archive.org/web/20120122031423/http://www.agdnutrition.com/d3-story.html |date=22 January 2012 }} 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 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 [[Biology:Lichen|lichen]]s, which is suitable for vegans.<ref>{{cite web | url = http://www.vitashine-d3.com/ | title = Vitashine Vegan Vitamin D3 Supplements | access-date = 15 March 2013 | url-status = live | archive-url = https://web.archive.org/web/20130304133936/http://www.vitashine-d3.com/ | archive-date = 4 March 2013 }}</ref><ref name="Wang">{{cite journal | vauthors = Wang T, Bengtsson G, Kärnefelt I, Björn LO | title = Provitamins and vitamins D<sub>2</sub>and D<sub>3</sub>in Cladina spp. over a latitudinal gradient: possible correlation with UV levels | journal = Journal of Photochemistry and Photobiology B: Biology | volume = 62 | issue = 1–2 | pages = 118–22 | date = September 2001 | pmid = 11693362 | doi = 10.1016/s1011-1344(01)00160-9 | url = http://lup.lub.lu.se/luur/download?func=downloadFile&recordOId=133512&fileOId=624375 | archive-url = https://web.archive.org/web/20121028160041/http://lup.lub.lu.se/luur/download?func=downloadFile&recordOId=133512&fileOId=624375 | url-status = live | archive-date = 28 October 2012 }}</ref>

==Stability==
Cholecalciferol is very sensitive to [[Physics:Ultraviolet|UV radiation]] and will rapidly, but reversibly, break down to form supra-sterols, which can further irreversibly convert to [[Chemistry:Ergosterol|ergosterol]].{{citation needed|date=December 2012}}

==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>{{cite conference |title=CHOLECALCIFEROL: A UNIQUE TOXICANT FOR RODENT CONTROL |url=https://digitalcommons.unl.edu/vpc11/22/ |conference=Proceedings of the Eleventh Vertebrate Pest Conference (1984) |publisher=University of Nebraska Lincoln |date=March 1984 |quote=Cholecalciferol is an acute (single-feeding) and/or chronic (multiple-feeding) rodenticide toxicant with unique activity for controlling commensal rodents including anticoagulant-resistant rats. Cholecalciferol differs from conventional acute rodenticides in that no bait shyness is associated with consumption and time to death is delayed, with first dead rodents appearing 3-4 days after treatment. |access-date=27 August 2019 |archive-url=https://web.archive.org/web/20190827013804/https://digitalcommons.unl.edu/vpc11/22/ |archive-date=27 August 2019 |url-status=live }}</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 [[Medicine:Kidney failure|kidney failure]], cardiac abnormalities, [[Medicine:Hypertension|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."<ref name=merckvet2014/> High-dose cholecalciferol will tend to rapidly accumulate in adipose tissue yet release more slowly<ref name=bjn20070309>{{cite journal | vauthors = Brouwer DA, van Beek J, Ferwerda H, Brugman AM, van der Klis FR, van der Heiden HJ, Muskiet FA | title = Rat adipose tissue rapidly accumulates and slowly releases an orally-administered high vitamin D dose | journal = The British Journal of Nutrition | volume = 79 | issue = 6 | pages = 527–532 | date = June 1998 | pmid = 9771340 | doi = 10.1079/BJN19980091 | quote = We investigated the effect of oral high-dose cholecalciferol on plasma and adipose tissue cholecalciferol and its subsequent release, and on plasma 25-hydroxyvitamin D (25(OH)D).{{nbsp}}... We conclude that orally-administered cholecalciferol rapidly accumulates in adipose tissue and that it is very slowly released while there is energy balance. | doi-access = free }}</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, [[Biology:Common brushtail possum|possums]] have become a significant pest animal. For possum control, cholecalciferol has been used as the active ingredient in lethal baits.<ref>{{cite web | url=https://sds.rentokil-initial.com/sds/files/NZ-Rentokil-Pestoff_Decal_Possum_Bait-EN-SDS_01_CLP.pdf | title=Pestoff DECAL Possum Bait - Rentokil Initial Safety Data Sheets | access-date=10 May 2020 | archive-date=15 January 2021 | archive-url=https://web.archive.org/web/20210115134720/https://sds.rentokil-initial.com/sds/files/NZ-Rentokil-Pestoff_Decal_Possum_Bait-EN-SDS_01_CLP.pdf | url-status=dead }}</ref> The [[Chemistry:Median lethal dose|LD<sub>50</sub>]] is 16.8&nbsp;mg/kg, but only 9.8&nbsp;mg/kg if calcium carbonate is added to the bait.<ref>{{cite journal | vauthors = Morgan D | title = Field efficacy of cholecalciferol gel baits for possum (Trichosurus vulpecula) control | journal = New Zealand Journal of Zoology | volume = 33 | issue = 3 | pages = 221–8 | year = 2006 | doi = 10.1080/03014223.2006.9518449 | s2cid = 83765759 }}</ref><ref>{{cite journal |vauthors=Jolly SE, Henderson RJ, Frampton C, Eason CT | title = Cholecalciferol Toxicity and Its Enhancement by Calcium Carbonate in the Common Brushtail Possum | journal = Wildlife Research | volume=22 | issue=5 | pages = 579–83 | year = 1995 | doi = 10.1071/WR9950579 }}</ref> Kidneys and heart are target organs.<ref>{{cite web| url=http://www.kiwicare.co.nz/assets/Uploads/SDS/NO-Possums-Cholecalciferol-Gel-Bait2.pdf| title=Kiwicare Material Safety Data Sheet| url-status=dead| archive-url=https://web.archive.org/web/20130210101310/http://kiwicare.co.nz/assets/Uploads/SDS/NO-Possums-Cholecalciferol-Gel-Bait2.pdf| archive-date=10 February 2013}}</ref> LD<sub>50</sub> 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.<ref name=henderson2000>R. J. Henderson and C. T. Eason (2000), [https://www.publish.csiro.au/wr/wr99048 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 LD<sub>50</sub> as high as 88&nbsp;mg/kg or as low as 2&nbsp;[[Microgram|mcg]]/kg reported for dogs.<ref name=peterson2013>Michael E.Peterson & Kerstin Fluegeman, [https://www.sciencedirect.com/science/article/abs/pii/S1938973613000287 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 ([[Chemistry:Warfarin|Warfarin]] and [[Chemistry:Congener|congeners]]) or [[Chemistry:Bromethalin|Bromethalin]],<ref name=kocher2010>{{cite journal | vauthors = Kocher DK, Kaur G, Banga HS, Brar RS |title=Histopathological Changes in Vital Organs of House Rats Given Lethal Dose of Cholecalciferol (Vitamin D3) |journal=Indian Journal of Animal Research |volume=2 |issue=3 |pages=193–6 |year=2010 |doi= |issn=0367-6722 |quote=Use of cholecalciferol as a rodenticide in bait lowered the risk of secondary poisoning and minimized the toxicity of non-target species }}</ref> and that relay toxicosis (poisoning by eating a poisoned animal) has not been documented.<ref name=merckvet2014>{{cite web |url= https://www.merckvetmanual.com/toxicology/rodenticide-poisoning/cholecalciferol |title=Merck Veterinary Manual - Rodenticide Poisoning: Introduction | vauthors = Khan SA, Schell MM |date=November 2014 |access-date=10 October 2021 |quote=''Incidence of vitamin D3 toxicosis in animals is relatively less than that of anticoagulant and bromethalin toxicosis. Relay toxicosis from vitamin D3 has not been documented.'' }}</ref> Nevertheless, the same source reports that use of cholecalciferol in [[Biology:Rodenticide|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.<ref name=merckvet2014/>

== See also ==
* [[Medicine:Hypervitaminosis D|Hypervitaminosis D]], Vitamin D poisoning
* [[Chemistry:Ergocalciferol|Ergocalciferol]], vitamin D<sub>2</sub>.
* 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, a kidney [[Biology:Enzyme|enzyme]] that converts calcifediol to calcitriol.

== References ==
{{Reflist}}

== 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}}
{{Terpenoids}}

[[Category:Cyclopentanes]]
[[Category:CYP2D6 inhibitors]]
[[Category:Polyenes]]
[[Category:Rodenticides]]
[[Category:Secosteroids]]
[[Category:Vitamers]]
[[Category:Vitamin D]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Vinylidene compounds]]

{{Sourceattribution|Cholecalciferol}}