Wikipedia

Calcifediol

"Calcidiol" redirects here. For the drug marketed as "Calcidol", see Ergocalciferol.

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]

Calcifediol
Skeletal formula of calcifediol
Ball-and-stick model of the calcifediol molecule
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 Edit this at Wikidata
KEGG
MeSH Calcifediol
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 ☒N
    Key: JWUBBDSIWDLEOM-DTOXIADCSA-N ☒N
  • 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).
☒N verify (what is checkY☒N ?)

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

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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

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Main article: Vitamin D § Recommended serum levels

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

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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

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

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|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

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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

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

Other Organisms

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Teleost Fish

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In teleost fish, calcifediol is predominantly converted to calcitriol in the liver, rather than in the kidneys[23] which means circulating levels of calcifediol can be undetectable and alternative measures of vitamin D status are required. There has been some success in using dietary calcifediol supplementation in salmonids to improve growth and food conversion ratio.[24]

References

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  1. ^ a b c d "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 7094913.223-7&rft.date=1982-05&rft_id=info:doi/10.1111/j.1432-1033.1982.tb06581.x&rft_id=info:pmid/7094913&rft_id=https://doi.org/10.1111%2Fj.1432-1033.1982.tb06581.x&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  2. ^ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.
  3. ^ a b c d e f g h i "Vitamin D". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. 11 February 2021. Retrieved 14 March 2022.
  4. ^ a b c d e f g h i j k l m "Office of Dietary Supplements - Vitamin D". ods.od.nih.gov. 9 October 2020. Retrieved 31 October 2020.
  5. ^ a b c d e f g h i 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 24529992.319-29&rft.date=2014-03&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968073#id-name=PMC&rft_id=info:pmid/24529992&rft_id=info:doi/10.1016/j.chembiol.2013.12.016&rft.aulast=Bikle&rft.aufirst=DD&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968073&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  6. ^ a b c 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 14005489.1697-1711&rft.date=2018-08&rft_id=https://api.semanticscholar.org/CorpusID:14005489#id-name=S2CID&rft_id=info:pmid/29713796&rft_id=info:doi/10.1007/s00198-018-4520-y&rft.aulast=Quesada-Gomez&rft.aufirst=JM&rft.au=Bouillon, R&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  7. ^ a b "Rayaldee (calcifediol) FDA Approval History - Drugs.com". Retrieved 4 March 2021.
  8. ^ a b c d 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 9500993. PMID 31589774.1985-1992&rft.date=2019-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500993#id-name=PMC&rft_id=info:pmid/31589774&rft_id=info:doi/10.1002/jbmr.3884&rft.aulast=Bouillon&rft.aufirst=R&rft.au=Bikle, D&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500993&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  9. ^ a b 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 18541563.1738-42&rft.date=2008-06&rft_id=info:doi/10.1093/ajcn/87.6.1738&rft_id=info:pmid/18541563&rft.aulast=Heaney&rft.aufirst=RP&rft.au=Armas, LA&rft.au=Shary, JR&rft.au=Bell, NH&rft.au=Binkley, N&rft.au=Hollis, BW&rft_id=https://doi.org/10.1093%2Fajcn%2F87.6.1738&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  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 22446158.95-102&rft.date=2012-07&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361592#id-name=PMC&rft_id=info:pmid/22446158&rft_id=info:doi/10.1016/j.abb.2012.02.016&rft.aulast=Adams&rft.aufirst=JS&rft.au=Hewison, M&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361592&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  11. ^ a b c d "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. ^ a b c 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 15585791.1706S - 9S&rft.date=2004-12&rft_id=info:doi/10.1093/ajcn/80.6.1706S&rft_id=info:pmid/15585791&rft.aulast=Heaney&rft.aufirst=RP&rft_id=https://doi.org/10.1093%2Fajcn%2F80.6.1706S&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  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. ^ a b c d 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 15671234.317-22&rft.date=2005-02&rft_id=info:doi/10.1093/jn/135.2.317&rft_id=info:pmid/15671234&rft.aulast=Hollis&rft.aufirst=BW&rft_id=https://doi.org/10.1093%2Fjn%2F135.2.317&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  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 17823429.645-51&rft.date=2007-09&rft_id=info:doi/10.1093/ajcn/86.3.645&rft_id=info:pmid/17823429&rft.aulast=Kimball&rft.aufirst=SM&rft.au=Ursell, MR&rft.au=O'Connor, P&rft.au=Vieth, R&rft_id=https://doi.org/10.1093%2Fajcn%2F86.3.645&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  19. ^ "Calcifediol". go.drugbank.com. Retrieved 7 March 2021.
  20. ^ a b c d 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 4310770.2032-7&rft.date=1969-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC297455#id-name=PMC&rft_id=info:pmid/4310770&rft_id=info:doi/10.1172/JCI106168&rft.aulast=Ponchon&rft.aufirst=G&rft.au=Kennan, AL&rft.au=DeLuca, HF&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC297455&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  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 4332591.56-61&rft.date=1972-01&rft_id=info:doi/10.1001/archinte.1972.00320010060005&rft_id=info:pmid/4332591&rft.aulast=Holick&rft.aufirst=MF&rft.au=DeLuca, HF&rft.au=Avioli, LV&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  23. ^ Lock, E.-J.; Waagbø, R.; Wendelaar Bonga, S.; Flik, G. (February 2010). "The significance of vitamin D for fish: a review". Aquaculture Nutrition. 16 (1): 100–116. Bibcode:2010AqNut..16..100L. doi:10.1111/j.1365-2095.2009.00722.x.100-116&rft.date=2010-02&rft_id=info:doi/10.1111/j.1365-2095.2009.00722.x&rft_id=info:bibcode/2010AqNut..16..100L&rft.aulast=Lock&rft.aufirst=E.-J.&rft.au=Waagbø, R.&rft.au=Wendelaar Bonga, S.&rft.au=Flik, G.&rft_id=https://doi.org/10.1111%2Fj.1365-2095.2009.00722.x&rfr_id=info:sid/en.wikipedia.org:Calcifediol" class="Z3988">
  24. ^ Rider, S.; Verlhac-Trichet, V.; Constant, D.; Chenal, E.; Etheve, S.; Riond, B.; Schmidt-Posthaus, H.; Schoop, R. (April 2023). "Calcifediol is a safe and effective metabolite for raising vitamin D status and improving growth and feed conversion in rainbow trout". Aquaculture. 568: 739285. Bibcode:2023Aquac.56839285R. doi:10.1016/j.aquaculture.2023.739285.
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