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Calcifediol

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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 100.039.067Edit 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 theirstandard state(at 25 °C [77 °F], 100 kPa).

Calcifediol,also known ascalcidiol,25-hydroxycholecalciferol,or25-hydroxyvitamin D3(abbreviated25(OH)D3),[1]is a form ofvitamin Dproduced in theliverbyhydroxylationofvitamin D3(cholecalciferol) by the enzymevitamin D 25-hydroxylase.[3][4][5]Calcifediol can be further hydroxylated by theenzyme25(OH)D-1α-hydroxylase,primarily in the kidney, to formcalcitriol(1,25-(OH)2D3), which is the active hormonal form of vitamin D.[3][4][5]

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

Biology[edit]

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 ofCYP2R1,present inmicrosomes,although other enzymes such asmitochondrialCYP27A1can contribute.[5][8]Variations in the expression and activity of CYP2R1, such as low levels inobesity,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 anelimination half-lifeof 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 enzymatic25(OH)D-1α-hydroxylasereaction is performed exclusively byCYP27B1,which is highly expressed in the kidneys where it is principally regulated byparathyroid hormone,but also byFGF23and calcitriol itself.[3][5][8]CYP27B1 is also expressed in a number of other tissues, includingmacrophages,monocytes,keratinocytes,placentaandparathyroid glandand extra-renal synthesis of calcitriol from calcifediol has been shown to have biological effects in these tissues.[8][10]

Calcifediol is also converted into24,25-dihydroxycholecalciferolby 24-hydroxylation.[3]This enzymatic reaction is performed byCYP24A1which is expressed in many vitamin D target tissues including kidney, and is induced by calcitriol.[5]This will inactivate calcitriol tocalcitroic acid,but 24,25-(OH)2D3may have some biological actions itself.[5]

Blood test for vitamin D deficiency[edit]

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 diagnosevitamin 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 withosteoporosis,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 takeover-the-countervitamin D supplements in place of having screening.[15]

It is the mostsensitivemeasure, though experts have called for improved standardization and reproducibility across different laboratories.[4][13]According toMedlinePlus,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 broadreference rangeof 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[edit]

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 andrenal osteodystrophyand, with calcium, in primary or corticosteroid-inducedosteoporosis.[19]

Calcifediol may have advantages over cholecalciferol for the correction of vitamin D deficiency states.[6]A review of the results of ninerandomized control trialswhich 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 intestinalmalabsorption,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 secondaryhyperparathyroidismin patients withchronic kidney disease.[7]

Interactive pathway map[edit]

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

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VitaminDSynthesis_WP1531Go 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[edit]

Research in the laboratory ofHector DeLucaidentified 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 byMichael F. Holickin 1972.[22]

Research[edit]

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

References[edit]

  1. ^abcd"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.PMID7094913.
  2. ^"Drug and medical device highlights 2018: Helping you maintain and improve your health".Health Canada.14 October 2020.Retrieved17 April2024.
  3. ^abcdefghi"Vitamin D".Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. 11 February 2021.Retrieved14 March2022.
  4. ^abcdefghijklm"Office of Dietary Supplements - Vitamin D".ods.od.nih.gov.9 October 2020.Retrieved31 October2020.
  5. ^abcdefghiBikle 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.PMC3968073.PMID24529992.
  6. ^abcQuesada-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.PMID29713796.S2CID14005489.
  7. ^ab"Rayaldee (calcifediol) FDA Approval History - Drugs".Retrieved4 March2021.
  8. ^abcdBouillon 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.PMC9000993.PMID31589774.
  9. ^abHeaney 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.PMID18541563.
  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.PMC3361592.PMID22446158.
  11. ^abcd"25-hydroxy vitamin D test: Medline Plus".Retrieved 4 March 2021.
  12. ^"25HDN - Clinical: 25-Hydroxyvitamin D2 and D3, Serum".Mayo Clinic Labs. 2021.Retrieved4 March2021.
  13. ^abcHeaney 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.PMID15585791.
  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.PMC3972415.PMID24690624.
  15. ^abcdAmerican Society for Clinical Pathology,"Five Things Physicians and Patients Should Question",Choosing Wisely:an initiative of theABIM Foundation,American Society for Clinical Pathology,retrievedAugust 1,2013,which cites
  16. ^Bender DA (2003)."Vitamin D".Nutritional biochemistry of the vitamins.Cambridge: Cambridge University Press.ISBN978-0-521-80388-5.Retrieved December 10, 2008 throughGoogle 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.PMID15671234.
  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.PMID17823429.
  19. ^"Calcifediol".go.drugbank.Retrieved7 March2021.
  20. ^abcdCesareo 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.PMC6566727.PMID31064117.
  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.PMC297455.PMID4310770.
  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.PMID4332591.