Calcifediol

Last updated
Calcifediol
Calcidiol2.svg
Calcifediol 3D ball.png
Names
Preferred IUPAC name
(1S,3Z)-3-[(2E)-2-{(1R,3aS,7aR)-1-[(2R)-6-Hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene}ethylidene]-4-methylidenecyclohexan-1-ol
Other names
25-Hydroxyvitamin D3
25-Hydroxycholecalciferol
Calcidiol [1]
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.039.067 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Calcifediol
PubChem CID
UNII
  • InChI=1S/C27H44O2/c1-19-10-13-23(28)18-22(19)12-11-21-9-7-17-27(5)24(14-15-25(21)27)20(2)8-6-16-26(3,4)29/h11-12,20,23-25,28-29H,1,6-10,13-18H2,2-5H3/b21-11+,22-12-/t20-,23+,24-,25+,27-/m1/s1 X mark.svgN
    Key: JWUBBDSIWDLEOM-DTOXIADCSA-N X mark.svgN
  • InChI=1/C27H44O2/c1-19-10-13-23(28)18-22(19)12-11-21-9-7-17-27(5)24(14-15-25(21)27)20(2)8-6-16-26(3,4)29/h11-12,20,23-25,28-29H,1,6-10,13-18H2,2-5H3/b21-11+,22-12-/t20-,23+,24-,25+,27-/m1/s1
    Key: JWUBBDSIWDLEOM-DTOXIADCBI
  • O[C@@H]1CC(\C(=C)CC1)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CCCC(O)(C)C)C
Properties
C27H44O2
Molar mass 400.64 g/mol
Pharmacology
H05BX05 ( WHO )
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 (abbreviated 25(OH)D3), [1] is a form of vitamin D produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme vitamin D 25-hydroxylase. [3] [4] [5] Calcifediol can be further hydroxylated by the enzyme 25(OH)D-1α-hydroxylase, primarily in the kidney, to form calcitriol (1,25-(OH)2D3), which is the active hormonal form of vitamin D. [3] [4] [5]

Contents

Calcifediol is strongly bound in blood by the vitamin D-binding protein. [5] Measurement of serum calcifediol is the usual test performed to determine a person's vitamin D status, to show vitamin D deficiency or sufficiency. [4] [5] Calcifediol is available as an oral medication in some countries to supplement vitamin D status. [4] [6] [7]

Biology

Calcifediol is the precursor for calcitriol, the active form of vitamin D. [3] [4] It is synthesized in the liver, by hydroxylation of cholecalciferol (vitamin D3) at the 25-position. [3] This enzymatic 25-hydroxylase reaction is mostly due to the actions of CYP2R1, present in microsomes, although other enzymes such as mitochondrial CYP27A1 can contribute. [5] [8] Variations in the expression and activity of CYP2R1, such as low levels in obesity, affect circulating calcifediol. [8] Similarly, vitamin D2, ergocalciferol, can also be 25-hydroxylated to form 25-hydroxyergocalciferol, (ercalcidiol, 25(OH)D2); [1] both forms are measured together in blood as 25(OH)D. [3] [4]

At a typical intake of cholecalciferol (up to 2000 IU/day), conversion to calcifediol is rapid. When large doses are given (100,000 IU), it takes 7 days to reach peak calcifediol concentrations. [9] Calcifediol binds in the blood to vitamin D-binding protein (also known as gc-globulin) and is the main circulating vitamin D metabolite. [4] [5] Calcifediol has an elimination half-life of around 15 to 30 days. [4] [9]

Calcifediol is further hydroxylated at the 1-alpha-position in the kidneys to form 1,25-(OH)2D3, calcitriol. [3] [4] This enzymatic 25(OH)D-1α-hydroxylase reaction is performed exclusively by CYP27B1, which is highly expressed in the kidneys where it is principally regulated by parathyroid hormone, but also by FGF23 and calcitriol itself. [3] [5] [8] CYP27B1 is also expressed in a number of other tissues, including macrophages, monocytes, keratinocytes, placenta and parathyroid gland and extra-renal synthesis of calcitriol from calcifediol has been shown to have biological effects in these tissues. [8] [10]

Calcifediol is also converted into 24,25-dihydroxycholecalciferol by 24-hydroxylation. [3] This enzymatic reaction is performed by CYP24A1 which is expressed in many vitamin D target tissues including kidney, and is induced by calcitriol. [5] This will inactivate calcitriol to calcitroic acid, but 24,25-(OH)2D3 may have some biological actions itself. [5]

Blood test for vitamin D deficiency

In medical practice, a blood test for 25-hydroxy-vitamin D, 25(OH)D, is used to determine an individual's vitamin D status. [11] The name 25(OH)D refers to any combination of calcifediol (25-hydroxy-cholecalciferol), derived from vitamin D3, and ercalcidiol (25-hydroxy-ergocalciferol), [1] derived from vitamin D2. The first of these (also known as 25-hydroxy vitamin D3) is made by the body, or is sourced from certain animal foods or cholecalciferol supplements. The second (25-hydroxy vitamin D2) is from certain vegetable foods or ergocalciferol supplements. [11] Clinical tests for 25(OH)D often measure the total level of both of these two compounds together, generally without differentiating. [12]

This measurement is considered the best indicator of overall vitamin D status. [11] [13] [14] US labs generally report 25(OH)D levels as ng/mL. Other countries use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L. [4]

This test can be used to diagnose vitamin D deficiency, and is performed in people with high risk for vitamin D deficiency, when the results of the test can be used to support beginning replacement therapy with vitamin D supplements. [4] [15] Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be at greater risk for being vitamin D-deficient and so are more likely to have this test. [15] Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not usually requested for the entire population. [15] Physicians may advise low risk patients to take over-the-counter vitamin D supplements in place of having screening. [15]

It is the most sensitive measure, though experts have called for improved standardization and reproducibility across different laboratories. [4] [13] According to MedlinePlus, the recommended range of 25(OH)D is 20 to 40 ng/mL (50 to 100 nmol/L) though they recognize many experts recommend 30 to 50 ng/mL (75 to 125 nmol/L). [11] The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20 to 150 nmol/L (8-60 ng/mL) has also been suggested, [16] while other studies have defined levels below 80 nmol/L (32 ng/mL) as indicative of vitamin D deficiency. [17]

Increasing calcifediol levels up to levels of 80 nmol/L (32 ng/mL) are associated with increasing the fraction of calcium that is absorbed from the gut. [13] Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400 nmol/L (160 ng/mL). [18]

Supplementation

Calcifediol supplements have been used in some studies to improve vitamin D status. [4] Indications for their use include vitamin D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia, hypoparathyroidism, hypocalcemia and renal osteodystrophy and, with calcium, in primary or corticosteroid-induced osteoporosis. [19]

Calcifediol may have advantages over cholecalciferol for the correction of vitamin D deficiency states. [6] A review of the results of nine randomized control trials which compared oral doses of both, found that calcifediol was 3.2-fold more potent than cholecalciferol. [6] Calcifediol is better absorbed from the intestine and has greater affinity for the vitamin-D-binding protein, both of which increase its bioavailability. [20] Orally administered calcifediol has a much shorter half-life with faster elimination. [20] These properties may be beneficial in people with intestinal malabsorption, obesity, or treated with certain other medications. [20]

In 2016, the FDA approved a formulation of calcifediol (Rayaldee) 60 microgram daily as a prescription medication to treat secondary hyperparathyroidism in patients with chronic kidney disease. [7]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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VitaminDSynthesis WP1531.png Go to articleGo to articleGo to articleGo to articlego to articleGo to articleGo to articleGo to articlego to articlego to articlego to articlego to articleGo to articleGo to articlego to articleGo to articlego to articlego to articlego to articleGo to articlego to article
|alt=Vitamin D Synthesis Pathway (view / edit)]]
Vitamin D Synthesis Pathway (view / edit)
  1. ↑ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

History

Research in the laboratory of Hector DeLuca identified 25(OH)D in 1968 and showed that the liver was necessary for its formation. [21] The enzyme responsible for this synthesis, cholecalciferol 25-hydroxylase, was isolated in the same laboratory by Michael F. Holick in 1972. [22]

Research

Studies are ongoing comparing the effects of calcifediol with other forms of vitamin D including cholecalciferol in prevention and treatment of osteoporosis. [3] [20]

Related Research Articles

<span class="mw-page-title-main">Calcium metabolism</span> Movement and regulation of calcium ions in and out of the body

Calcium metabolism is the movement and regulation of calcium ions (Ca2+) in (via the gut) and out (via the gut and kidneys) of the body, and between body compartments: the blood plasma, the extracellular and intracellular fluids, and bone. Bone acts as a calcium storage center for deposits and withdrawals as needed by the blood via continual bone remodeling.

<span class="mw-page-title-main">Cholecalciferol</span> Vitamin D3, a chemical compound

Cholecalciferol, also known as vitamin D3 and colecalciferol, is a type of vitamin D that is made by the skin when exposed to sunlight; it is found in some foods and can be taken as a dietary supplement.

<span class="mw-page-title-main">Ergocalciferol</span> Vitamin D2, a chemical compound

Ergocalciferol, also known as vitamin D2 and nonspecifically calciferol, is a type of vitamin D found in food and used as a dietary supplement. As a supplement it is used to prevent and treat vitamin D deficiency. This includes vitamin D deficiency due to poor absorption by the intestines or liver disease. It may also be used for low blood calcium due to hypoparathyroidism. It is used by mouth or injection into a muscle.

<span class="mw-page-title-main">Calcitriol</span> Active form of vitamin D

Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium (Ca2+) mainly by increasing the uptake of calcium from the intestines.

<span class="mw-page-title-main">Vitamin D toxicity</span> Human disease

Vitamin D toxicity, or hypervitaminosis D is the toxic state of an excess of vitamin D. The normal range for blood concentration in adults is 20 to 50 nanograms per milliliter (ng/mL).

<span class="mw-page-title-main">Secondary hyperparathyroidism</span> Medical condition

Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure. It is sometimes abbreviated "SHPT" in medical literature.

25-Hydroxyvitamin D 1-alpha-hydroxylase Mammalian protein found in Homo sapiens

25-Hydroxyvitamin D 1-alpha-hydroxylase also known as calcidiol 1-monooxygenase or cytochrome p450 27B1 (CYP27B1) or simply 1-alpha-hydroxylase is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene.

<span class="mw-page-title-main">Calcitroic acid</span> Chemical compound

Calcitroic acid (1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D3) is a major metabolite of 1α,25-dihydroxyvitamin D3 (calcitriol). Around 1980, scientists first reported the isolation of calcitroic acid from the aqueous extract of radioactively treated animals' livers and intestines. Subsequent researches confirmed calcitroic acid to be a part of enterohepatic circulation. Often synthesized in the liver and kidneys, calcitroic acid is generated in the body after vitamin D is first converted into calcitriol, an intermediate in the fortification of bone through the formation and regulation of calcium in the body. These pathways managed by calcitriol are thought to be inactivated through its hydroxylation by the enzyme CYP24A1, also called calcitriol 24-hydroxylase. Specifically, It is thought to be the major route to inactivate vitamin D metabolites. The hydroxylation and oxidation reactions will yield either calcitroic acid via the C24 oxidation pathway or 1,25(OH2)D3-26,23-lactone via the C23 lactone pathway.

<span class="mw-page-title-main">CYP24A1</span>

Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D3). It has also been identified as vitamin D3 24-hydroxylase.(EC 1.14.15.16)

<span class="mw-page-title-main">CYP2R1</span> Mammalian protein found in Homo sapiens

CYP2R1 is cytochrome P450 2R1, an enzyme which is the principal vitamin D 25-hydroxylase. In humans it is encoded by the CYP2R1 gene located on chromosome 11p15.2. It is expressed in the endoplasmic reticulum in liver, where it performs the first step in the activation of vitamin D by catalyzing the formation of 25-hydroxyvitamin D.

Vitamin D<sub>5</sub> Fat soluble vitamin

Vitamin D5 (sitocalciferol) is a form of vitamin D.

<span class="mw-page-title-main">24,25-Dihydroxycholecalciferol</span> Chemical compound

24,25-Dihydroxycholecalciferol, also known as 24,25-dihydroxyvitamin D3 and (24R)-hydroxycalcidiol (abbreviated as 24(R),25-(OH)2D3), is a compound which is closely related to 1,25-dihydroxyvitamin D3, the active form of vitamin D3. Like vitamin D3 itself and calcifediol (25-hydroxyvitamin D3), it is inactive as a hormone both in vitro and in vivo. It was first identified in 1972 in the laboratory of Hector DeLuca and Michael F. Holick.

<span class="mw-page-title-main">Vitamin D deficiency</span> Human disorder

Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D deficiency can also be caused by inadequate nutritional intake of vitamin D; disorders that limit vitamin D absorption; and disorders that impair the conversion of vitamin D to active metabolites, including certain liver, kidney, and hereditary disorders. Deficiency impairs bone mineralization, leading to bone-softening diseases, such as rickets in children. It can also worsen osteomalacia and osteoporosis in adults, increasing the risk of bone fractures. Muscle weakness is also a common symptom of vitamin D deficiency, further increasing the risk of fall and bone fractures in adults. Vitamin D deficiency is associated with the development of schizophrenia.

An endocrine bone disease is a bone disease associated with a disorder of the endocrine system. An example is osteitis fibrosa cystica.

<span class="mw-page-title-main">Alfacalcidol</span> Chemical compound

Alfacalcidol is an analogue of vitamin D used for supplementation in humans and as a poultry feed additive.

Vitamin D is a group of fat-soluble prohormones.

<span class="mw-page-title-main">Vitamin D</span> Group of fat-soluble secosteroids

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and for many other biological effects. In humans, the most important compounds in this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).

<span class="mw-page-title-main">Michael F. Holick</span> American physician–scientist

Michael F. Holick is an American adult endocrinologist, specializing in vitamin D, such as the identification of both calcidiol, the major circulating form of vitamin D, and calcitriol, the active form of vitamin D. His work has been the basis for diagnostic tests and therapies for vitamin D-related diseases. He is a professor of medicine at the Boston University Medical Center and editor-in-chief of the journal Clinical Laboratory.

<span class="mw-page-title-main">Vitamin D and neurology</span>

Vitamin D is a steroid hormone that plays a vital role in calcium and phosphate absorption. Recent studies show several associations between low levels of vitamin D, or hypovitaminosis D, and neuropsychiatric disorders, including Alzheimer's disease, autism, epilepsy, multiple sclerosis, Parkinson's disease, and schizophrenia.

Vitamin D3 24-hydroxylase (EC 1.14.15.16, CYP24A1) is an enzyme with systematic name calcitriol,NADPH:oxygen oxidoreductase (24-hydroxylating). This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 4 "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981". European Journal of Biochemistry. 124 (2): 223–7. May 1982. doi: 10.1111/j.1432-1033.1982.tb06581.x . PMID   7094913.
  2. ↑ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada . 14 October 2020. Retrieved 17 April 2024.
  3. 1 2 3 4 5 6 7 8 9 "Vitamin D". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. 11 February 2021. Retrieved 14 March 2022.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Office of Dietary Supplements - Vitamin D". ods.od.nih.gov. 9 October 2020. Retrieved 31 October 2020.
  5. 1 2 3 4 5 6 7 8 9 Bikle DD (March 2014). "Vitamin D metabolism, mechanism of action, and clinical applications". Chemistry & Biology. 21 (3): 319–29. doi:10.1016/j.chembiol.2013.12.016. PMC   3968073 . PMID   24529992.
  6. 1 2 3 Quesada-Gomez JM, Bouillon R (August 2018). "Is calcifediol better than cholecalciferol for vitamin D supplementation?". Osteoporosis International (review). 29 (8): 1697–1711. doi:10.1007/s00198-018-4520-y. PMID   29713796. S2CID   14005489.
  7. 1 2 "Rayaldee (calcifediol) FDA Approval History - Drugs.com" . Retrieved 4 March 2021.
  8. 1 2 3 4 Bouillon R, Bikle D (November 2019). "Vitamin D Metabolism Revised: Fall of Dogmas". Journal of Bone and Mineral Research (Review). 34 (11): 1985–1992. doi: 10.1002/jbmr.3884 . PMC   9000993 . PMID   31589774.
  9. 1 2 Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW (June 2008). "25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions". The American Journal of Clinical Nutrition. 87 (6): 1738–42. doi: 10.1093/ajcn/87.6.1738 . PMID   18541563.
  10. ↑ Adams JS, Hewison M (July 2012). "Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase". Arch Biochem Biophys. 523 (1): 95–102. doi:10.1016/j.abb.2012.02.016. PMC   3361592 . PMID   22446158.
  11. 1 2 3 4 "25-hydroxy vitamin D test: Medline Plus". Retrieved 4 March 2021.
  12. ↑ "25HDN - Clinical: 25-Hydroxyvitamin D2 and D3, Serum". Mayo Clinic Labs. 2021. Retrieved 4 March 2021.
  13. 1 2 3 Heaney RP (December 2004). "Functional indices of vitamin D status and ramifications of vitamin D deficiency". The American Journal of Clinical Nutrition. 80 (6 Suppl): 1706S–9S. doi: 10.1093/ajcn/80.6.1706S . PMID   15585791.
  14. ↑ Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP (April 2014). "Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials". BMJ. 348: g2035. doi:10.1136/bmj.g2035. PMC   3972415 . PMID   24690624.
  15. 1 2 3 4 American Society for Clinical Pathology, "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation , American Society for Clinical Pathology, retrieved August 1, 2013, which cites
  16. ↑ Bender DA (2003). "Vitamin D". Nutritional biochemistry of the vitamins. Cambridge: Cambridge University Press. ISBN   978-0-521-80388-5. Retrieved December 10, 2008 through Google Book Search.
  17. ↑ Hollis BW (February 2005). "Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D". The Journal of Nutrition. 135 (2): 317–22. doi: 10.1093/jn/135.2.317 . PMID   15671234.
  18. ↑ Kimball SM, Ursell MR, O'Connor P, Vieth R (September 2007). "Safety of vitamin D3 in adults with multiple sclerosis". The American Journal of Clinical Nutrition. 86 (3): 645–51. doi: 10.1093/ajcn/86.3.645 . PMID   17823429.
  19. ↑ "Calcifediol". go.drugbank.com. Retrieved 7 March 2021.
  20. 1 2 3 4 Cesareo R, Falchetti A, Attanasio R, Tabacco G, Naciu AM, Palermo A (May 2019). "Hypovitaminosis D: Is It Time to Consider the Use of Calcifediol?". Nutrients (Review). 11 (5): 1016. doi: 10.3390/nu11051016 . PMC   6566727 . PMID   31064117.
  21. ↑ Ponchon G, Kennan AL, DeLuca HF (November 1969). ""Activation" of vitamin D by the liver". The Journal of Clinical Investigation. 48 (11): 2032–7. doi:10.1172/JCI106168. PMC   297455 . PMID   4310770.
  22. ↑ Holick MF, DeLuca HF, Avioli LV (January 1972). "Isolation and identification of 25-hydroxycholecalciferol from human plasma". Archives of Internal Medicine. 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID   4332591.
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