| Cholecalciferol |
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IUPAC name
(3β,5Z,7E)-9,10-secocholesta-
5,7,10(19)-trien-3-ol
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Other names
vitamin D3, activated 7-dehydrocholesterol.
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| Identifiers |
| CAS number |
67-97-0 Y= Y |
| PubChem |
5280795 |
| ChemSpider |
4444353 N |
| UNII |
1C6V77QF41 Y |
| EC number |
200-673-2 |
| DrugBank |
DB00169 |
| ChEBI |
CHEBI:28940 N |
| ChEMBL |
CHEMBL1042 N |
| ATC code |
A11CC05 |
| Jmol-3D images |
Image 1 |
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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
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InChI=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 N
Key: QYSXJUFSXHHAJI-YRZJJWOYSA-N N
InChI=1/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
Key: QYSXJUFSXHHAJI-YRZJJWOYBL
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| Properties |
| Molecular formula |
C27H44O |
| Molar mass |
384.64 g/mol |
| Appearance |
White, needle-like crystals |
| Melting point |
83–86 °C |
| Boiling point |
496.4 °C |
N (verify) (what is: Y/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa) |
| Infobox references |
Cholecalciferol (also known as toxiferol) is a form of vitamin D, also called vitamin D3.[1][2]
It is structurally similar to steroids such as testosterone, cholesterol, and cortisol (though vitamin D3 itself is a secosteroid).
Contents
- 1 Forms
- 2 Metabolism
- 2.1 Regulation of metabolism
- 3 Industrial production
- 4 Dose
- 5 Stability
- 6 Preventative application
- 7 Toxicity
- 8 Interactive pathway map
- 9 See also
- 10 References
- 11 External links
Forms[edit]
Vitamin D3 has several forms:
- Cholecalciferol (sometimes called calciol) is an inactive, unhydroxylated form of vitamin D3).[citation needed]
- Calcifediol (also called calcidiol, hydroxycholecalciferol, 25-hydroxyvitamin D3, etc. and abbreviated 25(OH)D) is one of the forms measured in the blood to assess vitamin D status.[3]
- Calcitriol (also called 1,25-dihydroxyvitamin D3) is the active form of D3.[citation needed]
Metabolism[edit]
7-Dehydrocholesterol is the precursor of vitamin D3. Within the epidermal layer of skin,[4] 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 previtamin D3 undergoes a [1,7] antarafacial sigmatropic rearrangement [5] and therein finally isomerizes to form vitamin D3.
Cholecalciferol is then hydroxylated in the liver to become calcifediol (25-hydroxyvitamin D3).
Next, calcifediol is again hydroxylated, this time in the kidney, and becomes calcitriol (1,25-dihydroxyvitamin D3). Calcitriol is the most active hormone form of vitamin D3.
Regulation of metabolism[edit]
- Cholecalciferol is synthesized in the skin from 7-dehydrocholesterol under the action of ultraviolet B light. It reaches an equilibrium after several minutes depending on several factors including conditions of sunlight (latitude, season, cloud cover, altitude), age of skin, and color of 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 vitamin D3 produced in the skin or the vitamin D2 or D3 ingested.
- Hydroxylation in the kidneys of calcifediol to calcitriol by 1-alpha-hydroxylase is tightly regulated (stimulated by either parathyroid hormone or hypophosphatemia) and serves as the major control point in production of the most active circulating hormone calcitriol (1,25-dihydroxyvitamin D3).
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. Paraphrasing a more detailed explanation,[6] 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 stored in the skin of animals. The 7-dehydrocholesterol is then irradiated with ultra violet 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 vegetarians and vegans.[7][8]
An alternative compound is ergocalciferol (also known as vitamin D2) derived from the fungal sterol ergosterol.
Dose[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 they are: 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.[9] (Recommendations in Europe: 5 µg/d, in France: 25 µg) A growing body of researchers question whether the current recommended adequate levels are sufficient to meet physiological needs, particularly for individuals deprived of regular sun exposure or those at higher risk such as those with higher melanin content in the skin (i.e., those whose ancestors are African, Middle Eastern, Latin American, Mediterranean or Asian), the obese, and those who live far from the equator. The upper limit (UL) for vitamin D has been recommended as 4,000 IU daily. The 4,000-IU cut-off was determined by the Institute of Medicine in 2010 after reviewing the then-current medical literature, finding that the dose for lowest observed adverse effect level is 40,000 IU daily for at least 12 weeks,[10] 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.[10] 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.[9] 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.[11]
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.[12]
The 25-hydroxy vitamin D (calcifediol) blood test is used to determine how much vitamin D is in the body. The normal range of calcifediol is 30.0 to 74.0 ng/ml.[3]
"Vitamin D2 toxicity can result from regular excess intake of this vitamin, and may lead to hypercalcemia and excess bone loss. Individuals at particular risk include those with hyperparathyroidism, kidney disease, sarcoidosis, tuberculosis, or histoplasmosis. Chronic hypercalcemia may lead to serious or even life-threatening complications, and should be managed by a physician. Early symptoms of hypercalcemia may include nausea, vomiting, and anorexia (appetite/weight loss), followed by polyuria (excess urination), polydipsia (excess thirst), weakness, fatigue, somnolence, headache, dry mouth, metallic taste, vertigo, tinnitus (ear ringing), and ataxia (unsteadiness). Kidney function may become impaired, and metastatic calcifications (calcium deposition in organs throughout the body) may occur, particularly affecting the kidneys. Treatment involves stopping the intake of vitamin D or calcium, and lowering the calcium levels under strict medical supervision, with frequent monitoring of calcium levels. Acidification of urine and corticosteroids may be necessary."[13]
There are conflicting reports concerning the absorption of cholecalciferol (D3) versus ergocalciferol (D2), with some studies suggesting less efficacy of D2,[14] and others showing no difference.[15] At present, D2 and D3 doses are frequently considered interchangeable, but more research is needed to clarify this.
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]
Preventative application[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 cholecaliferol per day prevented colon cancer development.[16] In humans, with 400 IU daily, there was no effect.[17]
Toxicity[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."[18]
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.[19][20]
Kidneys and heart are target organs.[21]
Interactive pathway map[edit]
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Vitamin D Synthesis Pathway edit
- ^ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".
See also[edit]
- Hypervitaminosis D, Vitamin D poisoning
- Ergocalciferol, vitamin D2.
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, a kidney enzyme that converts calcifediol to calcitriol.
References[edit]
- ^ "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.
- ^ "cholecalciferol" at Dorland's Medical Dictionary
- ^ a b "25-hydroxy vitamin D test: Medline Plus". Retrieved 21 March 2010.
- ^ 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.
- ^ 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.
- ^ Vitamin D3 Story. Retrieved 8 April 2012.
- ^ "Vitashine Vegan Vitamin D3 Supplements". Retrieved 2013-03-15.
- ^ 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. Retrieved 2013-03-15.
- ^ a b DRIs for Calcium and Vitamin D
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Vitamin D: MedlinePlus Supplements with the National Academy of Sciences dosing recommendations at the Medline Plus website.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "Merck Veterinary Manual - Rodenticide Poisoning: Introduction".
- ^ 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.
- ^ 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.
- ^ "Kiwicare Material Safety Data Sheet".
External links[edit]
- NIST Chemistry WebBook page for cholecalciferol
- University of California TV - What’s a Vitamin D Deficiency?
- University of California TV - Dose-Response of Vitamin D and a Mechanism for Cancer Prevention
- Vitamin D metabolism, sex hormones, and male reproductive function.
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Vitamins (A11)
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| Fat soluble |
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A
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α-Carotene · β-Carotene · Retinol# · Tretinoin
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D
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D2 (Ergosterol, Ergocalciferol#) · D3 (7-Dehydrocholesterol, Previtamin D3, Cholecalciferol, 25-hydroxycholecalciferol, Calcitriol (1,25-dihydroxycholecalciferol), Calcitroic acid) · D4 (Dihydroergocalciferol) · D5 · D analogues (Alfacalcidol, Dihydrotachysterol, Calcipotriol, Tacalcitol, Paricalcitol)
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E
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Tocopherol (Alpha, Beta, Gamma, Delta) · Tocotrienol (Alpha, Beta, Gamma, Delta) · Tocofersolan
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K
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Naphthoquinone · Phylloquinone (K1) · Menaquinones (K2) · Menadione (K3)‡ · Menadiol (K4)
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| Water soluble |
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B
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B1 (Thiamine#) · B2 (Riboflavin#) · B3 (Niacin, Nicotinamide#) · B5 (Pantothenic acid, Dexpanthenol, Pantethine) · B6 (Pyridoxine#, Pyridoxal phosphate, Pyridoxamine) · B7 (Biotin) · B9 (Folic acid, Dihydrofolic acid, Folinic acid, L-methylfolate) · B12 (Cyanocobalamin, Hydroxocobalamin, Methylcobalamin, Cobamamide) · Choline
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C
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Ascorbic acid# · Dehydroascorbic acid
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| Combinations |
Multivitamins
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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noco, nuvi, sysi/epon, met
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Cholestanes, membrane lipids: sterols
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- Adosterol
- Cholecalciferol/Ergocalciferols
- Cholesterol
- Dihydrotachysterol
- Fusidic acid
- Lanosterol
- Phytosterols
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