Cholecalciferol
Encyclopedia
Cholecalciferol is a form of vitamin D
, also called vitamin D3 or calciol.
It is structurally similar to steroid
s such as testosterone
, cholesterol
, and cortisol
(though vitamin D3 itself is a secosteroid
).
is the precursor of vitamin D3 and forms cholecalciferol only after isomerization due to UV radiation exposure from the sun or artificial sources of UVB light.
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.
extracted from lanolin
found in sheep's wool. In foods where animal products are not desired, an alternative compound is ergocalciferol
(also known as vitamin D2) derived from the fungal sterol ergosterol
.
, where one IU is equivalent to 0.025 μg. Recommendations are: 15 micrograms (600 IU or International Units) daily for all individuals (males, female, pregnant/lactating women) under the age of 70 years-old. For all individuals older than 70 years, 20 micrograms daily (800 IU) is recommended. 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, Latin American, 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 toxicity had consistently occurred when doses of 40,000 IU daily were taken, and that there was a single case of toxicity above 10,000 IU daily; this case of toxicity occurred under circumstances which 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 number 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.
However, there also exist studies which disadvise from supplementing vitamin D if not really necessary: Vitamin D might support the emergence of allergies and adulterate already existing allergies and autoimmune diseases.
Also, there is a therapy for rickets
utilizing a single dose, called stoss therapy in Europe - taking from 300 000 IU (7500 μg) to 500 000 IU (12 500 μg), as a single dose, or two to four divided doses.
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.
"Vitamin D 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 corticosteroid
s may be necessary."
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.
and will rapidly, but reversibly, break down to form sura-sterols, which can further irreversibly convert to ergosterol
.
In New Zealand
, possum
s 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.
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
, also called vitamin D3 or calciol.
It is structurally similar to steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s such as testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, and cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
(though vitamin D3 itself is a secosteroid
Secosteroid
A secosteroid is a molecule similar to a steroid but with a "broken" ring. Etym: L. Seco, to cut, _ steroidSecosteroids are very similar in structure to steroids except that two of the B-ring carbon atoms of the typical four steroid rings are not joined, whereas in steroids they are.In humans, the...
).
Forms
Vitamin D3 has several forms:- Cholecalciferol, (sometimes called calciol) is an inactive, unhydroxylated form of vitamin D3)
- 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
- CalcitriolCalcitriolCalcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...
(also called 1,25-dihydroxyvitamin D3) is the active form of D3.
Metabolism
7-Dehydrocholesterol7-Dehydrocholesterol
7-Dehydrocholesterol is a zoosterol that functions in the serum as a cholesterol precursor, and is converted to vitamin D3 in the skin, therefore functioning as provitamin-D3. The presence of this compound in human skin enables humans to manufacture vitamin D3 from ultra-violet rays in the sun...
is the precursor of vitamin D3 and forms cholecalciferol only after isomerization due to UV radiation exposure from the sun or artificial sources of UVB light.
Cholecalciferol is then hydroxylated in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
to become calcifediol (25-hydroxyvitamin D3).
Next, calcifediol is again hydroxylated, this time in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, and becomes calcitriol
Calcitriol
Calcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...
(1,25-dihydroxyvitamin D3). Calcitriol is the most active hormone form of vitamin D3.
Regulation of metabolism
- 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 hepatocyteHepatocyteA hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s of cholecalciferol to calcifediol (25-hydroxycholecalciferol) by 25-hydroxylaseCYP2R1Vitamin D 25-hydroxylase also known as cytochrome P450 2R1 is an enzyme that in humans is encoded by the CYP2R1 gene.- Function :Vitamin D 25-hydroxylase is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved...
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-hydroxylase25-Hydroxyvitamin D3 1-alpha-hydroxylase25-Hydroxyvitamin D3 1-alpha-hydroxylase also known as cytochrome p450 27B1 is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene....
is tightly regulated (stimulated by either parathyroid hormoneParathyroid hormoneParathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
or hypophosphatemiaHypophosphatemiaHypophosphatemia is an electrolyte disturbance in which there is an abnormally low level of phosphate in the blood. The condition has many causes, but is most commonly seen when malnourished patients are given large amounts of carbohydrates, which creates a high phosphorus demand by cells,...
) and serves as the major control point in production of the most active circulating hormone calcitriolCalcitriolCalcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...
(1,25-dihydroxyvitamin D3).
As food fortification
Although cholecalciferol can be synthesized in the skin (see Metabolism), it is also a form of vitamin D added to fortify foods. Cholecalciferol is produced industrially by the irradiation of 7-dehydrocholesterol7-Dehydrocholesterol
7-Dehydrocholesterol is a zoosterol that functions in the serum as a cholesterol precursor, and is converted to vitamin D3 in the skin, therefore functioning as provitamin-D3. The presence of this compound in human skin enables humans to manufacture vitamin D3 from ultra-violet rays in the sun...
extracted from lanolin
Lanolin
Lanolin , also called Adeps Lanae, wool wax or wool grease, is a yellow waxy substance secreted by the sebaceous glands of wool-bearing animals. Most lanolin used by humans comes from domestic sheep...
found in sheep's wool. In foods where animal products are not desired, an alternative compound is ergocalciferol
Ergocalciferol
Ergocalciferol is a form of vitamin D, also called vitamin D2. It is marketed under various names including Deltalin , Drisdol and Calcidol...
(also known as vitamin D2) derived from the fungal sterol ergosterol
Ergosterol
Ergosterol is a sterol found in fungi, and named for ergot, a common name for the members of the fungal genus Claviceps from which ergosterol was first isolated. Ergosterol does not occur in plant or animal cells...
.
Dose
One gram of pure vitamin D3 is 40 000 000 (40x106) IUInternational unit
In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...
, where one IU is equivalent to 0.025 μg. Recommendations are: 15 micrograms (600 IU or International Units) daily for all individuals (males, female, pregnant/lactating women) under the age of 70 years-old. For all individuals older than 70 years, 20 micrograms daily (800 IU) is recommended. 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, Latin American, 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 toxicity had consistently occurred when doses of 40,000 IU daily were taken, and that there was a single case of toxicity above 10,000 IU daily; this case of toxicity occurred under circumstances which 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 number 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.
However, there also exist studies which disadvise from supplementing vitamin D if not really necessary: Vitamin D might support the emergence of allergies and adulterate already existing allergies and autoimmune diseases.
Also, there is a therapy for rickets
Rickets
Rickets is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, magnesium , phosphorus or calcium, potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries...
utilizing a single dose, called stoss therapy in Europe - taking from 300 000 IU (7500 μg) to 500 000 IU (12 500 μg), as a single dose, or two to four divided doses.
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.
"Vitamin D 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
Hyperparathyroidism
Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone . The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels...
, kidney disease, sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...
, tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, or histoplasmosis
Histoplasmosis
Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs...
. 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
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
(appetite/weight loss), followed by polyuria
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
(excess urination), polydipsia
Polydipsia
Polydipsia is a medical symptom in which the patient displays excessive thirst. The word derives from the Greek πολυδιψία, which is derived from πολύς + δίψα...
(excess thirst), weakness, fatigue, somnolence, headache, dry mouth, metallic taste, vertigo, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
(ear ringing), and ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(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 corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s may be necessary."
There are conflicting reports concerning the absorption of cholecalciferol (D3) versus ergocalciferol
Ergocalciferol
Ergocalciferol is a form of vitamin D, also called vitamin D2. It is marketed under various names including Deltalin , Drisdol and Calcidol...
(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.
Stability
Cholecalciferol is very sensitive to UV radiationUltraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
and will rapidly, but reversibly, break down to form sura-sterols, which can further irreversibly convert to ergosterol
Ergosterol
Ergosterol is a sterol found in fungi, and named for ergot, a common name for the members of the fungal genus Claviceps from which ergosterol was first isolated. Ergosterol does not occur in plant or animal cells...
.
Preventative application
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. In humans, with 400 IU daily, there was no effect.Toxicity
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
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...
, possum
Possum
A possum is any of about 70 small to medium-sized arboreal marsupial species native to Australia, New Guinea, and Sulawesi .Possums are quadrupedal diprotodont marsupials with long tails...
s 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.
See also
- Hypervitaminosis DHypervitaminosis DHypervitaminosis D is a state of vitamin D toxicity.The recommended daily allowance is 400 IU per day. Overdose has been observed at 1925 µg/d...
, Vitamin D poisoning - ErgocalciferolErgocalciferolErgocalciferol is a form of vitamin D, also called vitamin D2. It is marketed under various names including Deltalin , Drisdol and Calcidol...
, vitamin D2. - 25-Hydroxyvitamin D3 1-alpha-Hydroxylase25-Hydroxyvitamin D3 1-alpha-hydroxylase25-Hydroxyvitamin D3 1-alpha-hydroxylase also known as cytochrome p450 27B1 is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene....
, a kidney enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that converts calcifediol to calcitriol.