Cholecalciferol

Cholecalciferol

Names
IUPAC names (3β,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol
Other names vitamin D3, activated 7-dehydrocholesterol
Identifiers
CAS Number	67-97-0 Y=  Y
ChEBI	CHEBI:28940 N
ChEMBL	ChEMBL1042 N
ChemSpider	4444353 N
DrugBank	DB00169 Y
EC Number	200-673-2
Jmol 3D model	Interactive image
PubChem	5280795
UNII	1C6V77QF41 Y
InChI 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
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
Properties
Chemical formula	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)
Solubility in water	Practically insoluble in water, freely soluble in Abs. Ethanol, Methanol and some other organic solvents. Slightly soluble in vegetable oils.
Pharmacology
ATC code	A11CC05
Vapor pressure	{{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Cholecalciferol (/ˌkoʊləkælˈsɪfərɒl/) (vitamin D₃) is one of the five forms of vitamin D. 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

7-Dehydrocholesterol is the precursor of cholecalciferol. Within the epidermal layer of skin, 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 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.

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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway edit]]

File:VitaminDSynthesis WP1531.png

Vitamin D Synthesis Pathway edit

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. 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 is also produced industrially for use in vitamin supplements from lichens, which is suitable for vegans.

Oral supplementation

To prevent or treat deficiency

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) between the ages of 1 and 70 years old, inclusive. For all individuals older than 70 years, 20 µg/d (800 IU per day) is recommended.
• 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, 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. 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. 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.

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 = 12.5 mg), in a single dose, or in two to four divided doses.

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

To prevent disease

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 significant 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.

Use as rodenticide

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."

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.

Kidneys and heart are target organs.

Stability

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.

See also

• Hypervitaminosis D, Vitamin D poisoning
• Ergocalciferol, vitamin D₂.
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, a kidney enzyme that converts calcifediol to calcitriol.

External links

• 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.