Cholecalciferol

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Cholecalciferol
Cholecalciferol.svg
Cholecalciferol-vitamin-D3-from-xtal-3D-sticks.png
Names
IUPAC names
(3β,5Z,7E)-9,10-secocholesta-
5,7,10(19)-trien-3-ol
Other names
vitamin D3, activated 7-dehydrocholesterol.
Identifiers
ATC code A11CC05
67-97-0 YesY=  YesY
ChEBI CHEBI:28940 N
ChEMBL ChEMBL1042 N
ChemSpider 4444353 N
DrugBank DB00169 YesY
EC number 200-673-2
Jmol-3D images Image
PubChem 5280795
UNII 1C6V77QF41 YesY
Properties
C27H44O
Molar mass 384.64 g/mol
Appearance White, needle-like crystals
Melting point 83 to 86 °C (181 to 187 °F; 356 to 359 K)
Boiling point 496.4 °C (925.5 °F; 769.5 K)
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N verify (what isYesY/N?)
Infobox references

Cholecalciferol (toxiferol, vitamin D3) is one of the five forms of vitamin D.[1][2] It is a secosteroid, that is, a steroid molecule with one ring open. This and all forms of vitamin D are misnamed: vitamins by definition are essential organic compounds which cannot be synthesized by the body and must be ingested; cholecalciferol is synthesized by the body, and functions as a prehormone. 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[edit]

7-Dehydrocholesterol is the precursor of cholecalciferol. Within the epidermal layer of skin,[3] 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 [4] and therein finally isomerizes to form vitamin D3. 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:

  • 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 either parathyroid hormone or hypophosphatemia and serves as the major control point in the production of the active circulating hormone calcitriol (1,25-dihydroxyvitamin D3).

Click on icon in lower right corner to open. Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Vitamin D Synthesis Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531". 

Industrial production[edit]

Cholecalciferol is produced industrially for use in vitamin supplements and to fortify foods by the ultraviolet irradiation of 7-dehydrocholesterol extracted from lanolin found in sheep's wool.[5] 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 synth.png

Cholecalciferol is also produced industrially for use in vitamin supplements from lichens, which is suitable for vegans.[6][7]

Oral supplementation[edit]

To prevent or treat deficiency[edit]

One gram is 40,000,000 (40x106) IU, equivalently 1 IU is 0.025 µg.

Recommendations vary depending on the country:

  • In the US: 15 µg/d (600 IU per day) for all individuals (males, female, pregnant/lactating women) under the age of 70 years-old. For all individuals older than 70 years, 20 µg/d (800 IU per day) is recommended.[8]
  • In the EU: 20 µg/d
  • In France: 25 µg)

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,[9] 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.[9] The Institute of Medicine did not find evidence of toxicity between 4,000 IU and 10,000 IU, so the 4,000-IU figure is more of an estimate than a number based on evidence of toxicity above 4,000 IU.[8] 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.[10]

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 = 1.25 mg), in a single dose, or in two to four divided doses.[11]

There are conflicting reports concerning the absorption of cholecalciferol (D3) versus ergocalciferol (D2), with some studies suggesting less efficacy of D2,[12] and others showing no difference.[13] At present, D2 and D3 doses are frequently considered interchangeable, but more research is needed to clarify this.

To prevent disease[edit]

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.[14] In humans, with 400 IU daily, there was no effect;[15] however, significant correlation exists between low levels of blood serum cholecalciferol and higher rates of various cancers, multiple sclerosis, tuberculosis, heart disease, and diabetes.[16]

Objecting to the conclusions of the results of recent randomized clinical trials (RCTs) examining whether vitamin D supplementation can reduce the likelihood of various diseases, which used "low dose, lack of compliance, cross-over, and poor follow-up" and had concluded that Vitamin D supplementation is unnecessary for most people, Dr. Ed Gorham from the UCSD Department of Family and Preventive Medicine: "Many epidemiologic advances have been based on observational studies. It is fortunate we didn't rely on RCTs to recognize the hazards of cigarette smoking or second-hand smoke, which were determined through case-control studies and cohort studies respectively. Do our ethics allow us to withhold vitamin D to only 800 IU in a placebo group such as that of VITAL? 800 IU would on average raise baseline serum vitamin D levels barely 8 ng/ml. VITAL will place half the participants at risk of what is finally becoming regarded by vitamin D experts as the vitamin D deficiency syndrome. Likewise, the meager 2,000 IU per day given to the treatment group in Vital will still fall short of many of the benefits of vitamin D sufficiency which become apparent when patients achieve a 40-60ng/ml 25(OH)D range."

Use as rodenticide[edit]

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."[17]

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.[18][19]

Kidneys and heart are target organs.[20]

Stability[edit]

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.[citation needed]

See also[edit]

References[edit]

  1. ^ "Nomenclature of Vitamin D. Recommendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)" reproduced at the Queen Mary, University of London website. Retrieved 21 March 2010.
  2. ^ "cholecalciferol" at Dorland's Medical Dictionary
  3. ^ Norman, Anthony W. (1998) Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D:integral components of the vitamin D endocrine system. Am J Clin Nutr;67:1108–10.
  4. ^ Okamura, W. H., Elnagar, H. Y., Ruther, M. & S. Dobreff. (1993). "Thermal [1,7]-sigmatropic shift of previtamin D3 to vitamin D3: synthesis and study of pentadeuterio derivatives". Journal of Organic Chemistry 58 (3): 600–610. doi:10.1021/jo00055a011. 
  5. ^ Vitamin D3 Story. Retrieved 8 April 2012.
  6. ^ "Vitashine Vegan Vitamin D3 Supplements". Retrieved 2013-03-15. 
  7. ^ Ting Wang; Göran Bengtsson; Ingvar Kärnefelt; Lars Olof Björn (Sep 1, 2001). "Provitamins and vitamins D₂ and D₃ in Cladina spp. over a latitudinal gradient: possible correlation with UV levels". J Photochem Photobiol B. (Department of Plant physiology, Lund University, Sweden) 62 (1–2): 118–22. doi:10.1016/s1011-1344(01)00160-9. PMID 11693362. Retrieved 2013-03-15. 
  8. ^ a b DRIs for Calcium and Vitamin D
  9. ^ a b Vieth R (May 1999). "Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety". Am. J. Clin. Nutr. 69 (5): 842–56. PMID 10232622. 
  10. ^ van Groningen L, Opdenoordt S, van Sorge A, Telting D, Giesen A, de Boer H (April 2010). "Cholecalciferol loading dose guideline for vitamin D-deficient adults". Eur. J. Endocrinol. 162 (4): 805–11. doi:10.1530/EJE-09-0932. PMID 20139241. 
  11. ^ Shah BR, Finberg L (September 1994). "Single-day therapy for nutritional vitamin D-deficiency rickets: a preferred method". J. Pediatr. 125 (3): 487–90. doi:10.1016/S0022-3476(05)83303-7. PMID 8071764. 
  12. ^ Armas LA, Hollis BW, Heaney RP (November 2004). "Vitamin D2 is much less effective than vitamin D3 in humans". J. Clin. Endocrinol. Metab. 89 (11): 5387–91. doi:10.1210/jc.2004-0360. PMID 15531486. 
  13. ^ Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD (March 2008). "Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D". J. Clin. Endocrinol. Metab. 93 (3): 677–81. doi:10.1210/jc.2007-2308. PMC 2266966. PMID 18089691. 
  14. ^ 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 (October 2008). "Dietary induction of colonic tumors in a mouse model of sporadic colon cancer". Cancer Res. 68 (19): 7803–10. doi:10.1158/0008-5472.CAN-08-1209. PMID 18829535. 
  15. ^ 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 (February 2006). "Calcium plus vitamin D supplementation and the risk of colorectal cancer". N. Engl. J. Med. 354 (7): 684–96. doi:10.1056/NEJMoa055222. PMID 16481636. 
  16. ^ Cedric F. Garland, DrPH, Frank C. Garland, PhD, Edward D. Gorham, PhD, MPH, Martin Lipkin, MD, Harold Newmark, ScD, Sharif B. Mohr, MPH, and Michael F. Holick, MD, PhD (February 2006). "The Role of Vitamin D in Cancer Prevention". Am J Public Health 96 (2): 252–261. doi:10.2105/AJPH.2004.045260. PMC 1470481. PMID 16380576. 
  17. ^ "Merck Veterinary Manual - Rodenticide Poisoning: Introduction". 
  18. ^ Morgan D (2006). "Field efficacy of cholecalciferol gel baits for possum (Trichosurus vulpecula) control". New Zealand Journal of Zoology 33 (3): 221–8. doi:10.1080/03014223.2006.9518449. 
  19. ^ Jolly SE, Henderson RJ, Frampton C, Eason CT (1995). "Cholecalciferol Toxicity and Its Enhancement by Calcium Carbonate in the Common Brushtail Possum". Wildlife Research 22 (5): 579–83. doi:10.1071/WR9950579. 
  20. ^ "Kiwicare Material Safety Data Sheet" (PDF). 

External links[edit]