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Cholecalciferol, also known as vitamin D3 and colecalciferol, is a type of
vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...
that is made by the skin when exposed to sunlight; it is found in some foods and can be taken as a
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
. Cholecalciferol is made in the skin following UVB light exposure. It is converted in the liver to calcifediol (25-hydroxyvitamin D) which is then converted in the kidney to calcitriol (1,25-dihydroxyvitamin D). One of its actions is to increase
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
uptake by the intestines. It is found in food such as some
fish Fish are Aquatic animal, aquatic, craniate, gill-bearing animals that lack Limb (anatomy), limbs with Digit (anatomy), digits. Included in this definition are the living hagfish, lampreys, and Chondrichthyes, cartilaginous and bony fish as we ...
, beef liver, eggs, and cheese. Plant and cow milk, fruit juice, yogurt, and margarine also may have cholecalciferol added to them in some countries, including the United States. Cholecalciferol can be taken as an oral dietary supplement to prevent vitamin D deficiency or as a medication to treat associated diseases, including
rickets Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
. It is also used for
familial hypophosphatemia X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short st ...
,
hypoparathyroidism Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary m ...
that is causing
low blood calcium Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol ...
, and Fanconi syndrome. Vitamin-D supplements may not be effective in people with severe
kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...
. Excessive doses in humans can result in vomiting, constipation, weakness, and confusion. Other risks include
kidney stones Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a calculus (medicine), solid piece of material (kidney stone) develops in the urinary tract. Kidney stones typically form in the kidney and leave the ...
. Doses greater than 40,000 IU (1,000μg) per day are generally required before high blood calcium occurs. Normal doses, 800–2000 IU per day, are safe in
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
. Cholecalciferol was first described in 1936. It is on the World Health Organization's List of Essential Medicines. In 2020, it was the 60th most commonly prescribed medication in the United States, with more than 11million prescriptions. Cholecalciferol is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...
and
over the counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
.


Medical uses

Cholecalciferol appears to stimulate the body's interferon type I signaling system that protects against bacteria and viruses, unlike Vitamin D2.


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 calcitriol. This is important for maintaining calcium levels and promoting bone health and development. 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 (40x106) IU, equivalently 1 IU is 0.025 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 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 μg/d (800 IU per day) is recommended.DRIs for Calcium and Vitamin D
*In the EU (except France): 20 μg/d (800 IU per day) *In France: 25 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. Supplements are recommended for these groups of people. The
Institute of Medicine The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, Eng ...
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, 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. 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. 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. A much less common use of cholecalciferol therapy in
rickets Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
utilizes a single large dose and has been called ''stoss'' therapy. Treatment is given either orally or by
intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
of 300,000 IU (7,500 μg) to 500,000 IU (12,500 μg = 12.5 mg), in a single dose, or sometimes in two to four divided doses. There are concerns about the safety of such large doses. Low circulating vitamin D levels have been associated with lower total
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
levels in males. There has been shown information that Vitamin D supplmentation could potentially have evidence on total testosterone concentration, although more research is needed.


Other diseases

A meta-analysis of 2007 concluded that daily intake of 1000 to 2000 IU per day of vitamin D3 could reduce the incidence of colorectal cancer with minimal risk. 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. 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 correlations exist between low levels of blood serum cholecalciferol and higher rates of various cancers,
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This ...
,
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, ...
, heart disease, and diabetes, the consensus is that supplementing levels is not beneficial. It is thought that tuberculosis may result in lower levels. It, however, is not entirely clear how the two are related.


Biochemistry


Structure

Cholecalciferol is one of the five forms of
vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...
. Cholecalciferol is a
secosteroid A secosteroid () is a type of steroid with a "broken" ring. The word ''secosteroid ''derives from the Latin verb ''secare'' meaning "to cut", and 'steroid'. Secosteroids are alternatively described as a subclass of steroids; ; or derived from st ...
, that is, a steroid molecule with one ring open.


Mechanism of action

By itself cholecalciferol is inactive. It is converted to its active form by two
hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
s: the first in the liver, by CYP2R1 or
CYP27A1 CYP27A1 is a gene encoding a cytochrome P450 oxidase, and is commonly known as sterol 27-hydroxylase. This enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesis ...
, 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 The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterod ...
, a
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to ...
which regulates the synthesis of hundreds of proteins and is present in virtually every cell in the body.


Biosynthesis

Click on icon in lower right corner to open. 7-Dehydrocholesterol is the precursor of cholecalciferol. Within the epidermal layer of skin, 7-dehydrocholesterol undergoes an electrocyclic reaction as a result of UVB light at
wavelengths In physics, the wavelength is the spatial period of a periodic wave—the distance over which the wave's shape repeats. It is the distance between consecutive corresponding points of the same phase on the wave, such as two adjacent crests, tr ...
between 290 and 315 nm, with peak synthesis occurring between 295 and 300 nm. This results in the opening of the vitamin precursor B-ring through a conrotatory pathway making previtamin D3 (pre-cholecalciferol). In a process which is independent of UV light, the pre-cholecalciferol then undergoes a ,7antarafacial
sigmatropic A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular reaction. The name ''sigmatropic'' is the result of a compounding of the long ...
rearrangement and therein finally isomerizes to form vitamin D3. 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. Time of day, season, 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. Cholecalciferol can be produced in skin from the light emitted by the UV lamps in
tanning bed Indoor tanning involves using a device that emits ultraviolet radiation to produce a cosmetic tan. Typically found in tanning salons, gyms, spas, hotels, and sporting facilities, and less often in private residences, the most common device is a ...
s, 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 uses of tanning salons. Whether cholecalciferol and all forms of vitamin D are by definition "
vitamins A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
" 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. 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
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...
s 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).


Industrial production

Cholecalciferol is produced industrially for use in
vitamin supplement A multivitamin is a preparation intended to serve as a dietary supplement with vitamins, dietary minerals, and other nutritional elements. Such preparations are available in the form of tablets, capsules, pastilles, powders, liquids, or injectab ...
s and to fortify foods. As a
pharmaceutical drug A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
it is called cholecalciferol ( USAN) or colecalciferol ( INN,
BAN Ban, or BAN, may refer to: Law * Ban (law), a decree that prohibits something, sometimes a form of censorship, being denied from entering or using the place/item ** Imperial ban (''Reichsacht''), a form of outlawry in the medieval Holy Roman ...
). It is produced by the
ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
irradiation of 7-dehydrocholesterol extracted from lanolin found in sheep's
wool Wool is the textile fibre obtained from sheep and other mammals, especially goats, rabbits, and camelids. The term may also refer to inorganic materials, such as mineral wool and glass wool, that have properties similar to animal wool. ...
.Vitamin D3 Story.
Retrieved 8 April 2012.
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 In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of 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
lichen A lichen ( , ) is a composite organism that arises from algae or cyanobacteria living among filaments of multiple fungi species in a mutualistic relationship.


Stability

Cholecalciferol is very sensitive to
UV radiation Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiatio ...
and will rapidly, but reversibly, break down to form supra-sterols, which can further irreversibly convert to
ergosterol Ergosterol (ergosta-5,7,22-trien-3β-ol) is a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergosterol, t ...
.


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. The mechanism of high dose cholecalciferol is that it can produce "
hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6  mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcem ...
, which results in systemic calcification of soft tissue, leading to
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
,
cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
abnormalities,
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
, CNS depression, and GI upset. Signs generally develop within 18-36 hr of ingestion and can include depression,
loss of appetite Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
,
polyuria Polyuria () is excessive or an abnormally large production or passage of urine (greater than 2.5 L or 3 L over 24 hours in adults). Increased production and passage of urine may also be termed diuresis. Polyuria often appears in conjunction wi ...
, and
polydipsia Polydipsia is excessive thirst or excess drinking.Porth, C. M. (1990). ''Pathophysiology: Concepts of altered health states''. Philadelphia: J.B. Lippincott Company. The word derives from the Greek () "very thirsty", which is derived from (, " ...
." High-dose cholecalciferol will tend to rapidly accumulate in adipose tissue yet release more slowly which will tend to delay time of death for several days from the time that high-dose bait is introduced. In
New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island coun ...
,
possums Possum may refer to: Animals * Phalangeriformes, or possums, any of a number of arboreal marsupial species native to Australia, New Guinea, and Sulawesi ** Common brushtail possum (''Trichosurus vulpecula''), a common possum in Australian urban ...
have become a significant pest animal. For possum control, cholecalciferol has been used as the active ingredient in lethal baits. 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. LD50 of 4.4 mg/kg has been reported in rabbits, with lethality to almost all rabbits ingesting doses greater than 15 mg/kg.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.
Toxicity has been reported across a wide range of cholecalciferol dosages, with LD50 as high as 88 mg/kg or as low as 2  mcg/kg reported for dogs.Michael E.Peterson & Kerstin Fluegeman
Cholecalciferol (Topic Review)
Topics in Companion Animal Medicine, Volume 28, Issue 1, February 2013, Pages 24-27.
Researchers have reported that the compound is less toxic to non-target species than earlier generations of anticoagulant rodenticides (
Warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
and congeners) or Bromethalin, and that relay toxicosis (poisoning by eating a poisoned animal) has not been documented. Nevertheless, the same source reports that use of cholecalciferol in
rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despi ...
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.


See also

* Hypervitaminosis D, Vitamin D poisoning * Ergocalciferol, vitamin D2. * 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, a kidney
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that converts calcifediol to calcitriol.


References


LED lights safer, more effective in producing Vitamin D3 than sunlight


External links


NIST Chemistry WebBook page for cholecalciferol

Vitamin D metabolism, sex hormones, and male reproductive function.
* {{portal bar, Food, Medicine Cyclopentanes CYP2D6 inhibitors Polyenes Rodenticides Secosteroids Vitamers Vitamin D World Health Organization essential medicines Wikipedia medicine articles ready to translate Vinylidene compounds