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Record Information
Version2.0
Creation Date2009-07-21 20:26:07 UTC
Update Date2014-12-24 20:25:49 UTC
Accession NumberT3D2692
Identification
Common NameCalcitriol
ClassSmall Molecule
DescriptionCalcitriol or 1,25-dihydroxycholecalciferol (abbreviated 1,25-(OH)2-D3) is the active form of vitamin D found in the body (vitamin D3). Calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (Abbott) and Decostriol (Mibe, Jesalis). It is produced in the kidneys via 25-hydroxyvitamin D-1 α-hydroxylase by conversion from 25-hydroxycholecalciferol (calcidiol). This is stimulated by a decrease in serum calcium, phosphate (PO43-) and parathyroid hormone (PTH) levels. It regulates calcium levels by increasing the absorption of calcium and phosphate from the gastrointestinal tract, increasing calcium and phosphate reabsorption in the kidneys and inhibiting the release of PTH. Calcitriol is also commonly used as a medication in the treatment of hypocalcemia and osteoporosis.
Compound Type
  • Antihypocalcemic Agent
  • Antihypoparathyroid Agent
  • Antithyroid Agent
  • Bone Density Conservation Agent
  • Calcium Channel Agonist
  • Drug
  • Essential Vitamin
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Nutraceutical
  • Organic Compound
  • Vitamin
  • Vitamin D
Chemical Structure
Thumb
Synonyms
Synonym
(1alpha,3beta,5Z,7e)-9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol
(1S,3R,5Z,7e)-9,10-Secocholesta-5,7,10-triene-1,3,25-triol
(3b,5Z,7E)-9,10-Secocholesta-5,7,10(19)-trienetriol
(5Z,7e)-(1S,3R)-9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol
1,25 Dihydroxycholecalciferol
1,25-DHCC
1,25-Dihydroxycholecalciferol
1,25-Dihydroxyvitamin D
1,25-Dihydroxyvitamin D3
1-alpha,25-Dihydroxyvitamin D3
1-alpha-25-Dihydroxyvitamin D3
1a,25-(OH)2D3
1a,25-Dihydroxycholecalciferol
1a,25-Dihydroxyvitamin D3
1alpha,25(OH)2D3
1alpha,25-Dihydroxycholecalciferol
1alpha,25-Dihydroxyvitamin D3
1α,25(OH)2D3
1α,25-dihydroxycholecalciferol
1α,25-dihydroxyvitamin D3
25-Dihydroxycholecalciferol
5-{2-[1-(5-hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-4-ylidene]-ethylidene}-4-methylene-cyclohexane-1,3-diol
Calcijex
Calcitriol Oral Solution
Calcitriolum
Decostriol
Dihydroxyvitamin D3
Ro 21-5535
Rocaltrol
Silkis
Soltriol
Topitriol
Toptriol
Vectical
Chemical FormulaC27H44O3
Average Molecular Mass416.637 g/mol
Monoisotopic Mass416.329 g/mol
CAS Registry Number32222-06-3
IUPAC Name(1R,3S,5Z)-5-{2-[(1R,3aS,4E,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohexane-1,3-diol
Traditional Namecalcitriol
SMILES[H]\C(\C(\[H])=C1/CCC[C@@]2(C)[C@@]1([H])CC[C@]2([H])[C@]([H])(C)CCCC(C)(C)O)=C1/C[C@@]([H])(O)C[C@]([H])(O)C1=C
InChI IdentifierInChI=1S/C27H44O3/c1-18(8-6-14-26(3,4)30)23-12-13-24-20(9-7-15-27(23,24)5)10-11-21-16-22(28)17-25(29)19(21)2/h10-11,18,22-25,28-30H,2,6-9,12-17H2,1,3-5H3/b20-10+,21-11-/t18-,22-,23-,24+,25+,27-/m1/s1
InChI KeyInChIKey=GMRQFYUYWCNGIN-NKMMMXOESA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as vitamin d and derivatives. Vitamin D and derivatives are compounds containing a secosteroid backbone, usually secoergostane or secocholestane.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassVitamin D and derivatives
Direct ParentVitamin D and derivatives
Alternative Parents
Substituents
  • Triterpenoid
  • Tertiary alcohol
  • Cyclic alcohol
  • Secondary alcohol
  • Organic oxygen compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Alcohol
  • Aliphatic homopolycyclic compound
Molecular FrameworkAliphatic homopolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Extracellular
  • Membrane
  • Mitochondria
Biofluid LocationsNot Available
Tissue Locations
  • Adrenal Medulla
  • Bladder
  • Fibroblasts
  • Gonads
  • Gut
  • Intestine
  • Kidney
  • Muscle
  • Pancreas
  • Placenta
  • Prostate
  • Skeletal Muscle
  • Skin
  • Spleen
  • Stratum Corneum
  • Testes
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point113-114°C
Boiling PointNot Available
SolubilityInsoluble
LogP5
Predicted Properties
PropertyValueSource
Water Solubility0.0067 g/LALOGPS
logP5.51ALOGPS
logP4.35ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)14.39ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area60.69 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity126.53 m³·mol⁻¹ChemAxon
Polarizability51.02 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0aba-2019200000-f91cfe8e2e00e1a8f6daJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-014i-2200139000-8f9b07740968867d2e47JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001j-0009100000-5d85e3fe2656c4f2c798JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001j-0239000000-16579742f7806ac7c580JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0080-3297000000-1ded6f55cc278e5facb8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-0006900000-58dff5fdfef8e2a6c7c9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00kb-0009300000-93004eb4d3b2dee27fe8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-000t-1119000000-a3201818a6bc9ce6cac4JSpectraViewer
Toxicity Profile
Route of ExposureIntravenous, Oral. Rapidly absorbed from the intestine.
Mechanism of ToxicityThe mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)2-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)2-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells.
MetabolismThe first pathway involves 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)2-26,23S-lactone D3. The lactone appears to be the major metabolite circulating in humans. Route of Elimination: Enterohepatic recycling and biliary excretion of calcitriol occur. The metabolites of calcitriol are excreted primarily in feces. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces. Half Life: 5-8 hours
Toxicity ValuesLD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed to treat vitamin D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in patients with chronic renal failure undergoing dialysis. Also used in conjunction with calcium in the management and prevention of primary or corticosteroid-induced osteoporosis.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsOverdose evident in elevated blood calcium levels causing symptoms of anorexia, nausea and vomiting, polyuria, polydipsia, weakness, pruritus, and nervousness, potentially with irreversible calcification of soft tissue in the kidney and liver.
TreatmentThe treatment of acute accidental overdosage of Calcitriol should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and a low-calcium diet are also indicated in accidental overdosage. (13)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00136
HMDB IDHMDB01903
PubChem Compound ID5280453
ChEMBL IDCHEMBL846
ChemSpider ID4444108
KEGG IDC01673
UniProt IDNot Available
OMIM ID193100 , 259750 , 264700 , 277440 , 601199
ChEBI ID17823
BioCyc IDCALCITRIOL
CTD IDNot Available
Stitch IDCalcitriol
PDB IDVDX
ACToR IDNot Available
Wikipedia LinkCalcitriol
References
Synthesis Reference

Raymond E. Conrow, “Process for preparation of calcitriol lactone and related intermediates.” U.S. Patent US5457245, issued April, 1994.

MSDSLink
General References
  1. Shepard RM, Horst RL, Hamstra AJ, DeLuca HF: Determination of vitamin D and its metabolites in plasma from normal and anephric man. Biochem J. 1979 Jul 15;182(1):55-69. [227368 ]
  2. Mason RS, Frankel T, Chan YL, Lissner D, Posen S: Vitamin D conversion by sarcoid lymph node homogenate. Ann Intern Med. 1984 Jan;100(1):59-61. [6546329 ]
  3. Mallette LE: Case report: hypoparathyroidism with menses-associated hypocalcemia. Am J Med Sci. 1992 Jul;304(1):32-7. [1642251 ]
  4. Ott SM, Chesnut CH 3rd: Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med. 1989 Feb 15;110(4):267-74. [2913914 ]
  5. Bhan I, Shah A, Holmes J, Isakova T, Gutierrez O, Burnett SM, Juppner H, Wolf M: Post-transplant hypophosphatemia: Tertiary 'Hyper-Phosphatoninism'? Kidney Int. 2006 Oct;70(8):1486-94. Epub 2006 Aug 30. [16941023 ]
  6. Josephson MA, Schumm LP, Chiu MY, Marshall C, Thistlethwaite JR, Sprague SM: Calcium and calcitriol prophylaxis attenuates posttransplant bone loss. Transplantation. 2004 Oct 27;78(8):1233-6. [15502727 ]
  7. Gallagher JC, Goldgar D: Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A randomized controlled study. Ann Intern Med. 1990 Nov 1;113(9):649-55. [2221645 ]
  8. Lehmann B, Sauter W, Knuschke P, Dressler S, Meurer M: Demonstration of UVB-induced synthesis of 1 alpha,25-dihydroxyvitamin D3 (calcitriol) in human skin by microdialysis. Arch Dermatol Res. 2003 Apr;295(1):24-8. Epub 2003 Mar 11. [12709817 ]
  9. Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D: Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res. 2005 Sep 1;65(17):7917-25. [16140963 ]
  10. Kalkwarf HJ, Specker BL, Heubi JE, Vieira NE, Yergey AL: Intestinal calcium absorption of women during lactation and after weaning. Am J Clin Nutr. 1996 Apr;63(4):526-31. [8599316 ]
  11. Mason RS, Lissner D, Grunstein HS, Posen S: A simplified assay for dihydroxylated vitamin D metabolites in human serum: application to hyper- and hypovitaminosis D. Clin Chem. 1980 Mar;26(3):444-50. [6892691 ]
  12. Drugs.com [Link]
  13. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Recruited to promoters via its interaction with BAZ1B/WSTF which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.
Gene Name:
VDR
Uniprot ID:
P11473
Molecular Weight:
48288.64 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.0007 uMNot AvailableBindingDB 50200182
IC500.0008 uMNot AvailableBindingDB 50200182
IC500.00124 uMNot AvailableBindingDB 50200182
IC500.0093 uMNot AvailableBindingDB 50200182
IC500.013 uMNot AvailableBindingDB 50200182
Dissociation0.000065 uMNot AvailableBindingDB 50200182
References
  1. Reinhart GA: Vitamin D analogs: novel therapeutic agents for cardiovascular disease? Curr Opin Investig Drugs. 2004 Sep;5(9):947-51. [15503649 ]
  2. Thacher SM, Vasudevan J, Tsang KY, Nagpal S, Chandraratna RA: New dermatological agents for the treatment of psoriasis. J Med Chem. 2001 Feb 1;44(3):281-97. [11462969 ]
  3. Peleg S, Petersen KS, Suh BC, Dolan P, Agoston ES, Kensler TW, Posner GH: Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation. J Med Chem. 2006 Dec 14;49(25):7513-7. [17149880 ]
  4. Petersen KS, Dolan PM, Kensler TW, Peleg S, Posner GH: Low-calcemic, highly antiproliferative, 23-oxa ether analogs of the natural hormone 1 alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation. J Med Chem. 2007 Nov 15;50(23):5824-32. Epub 2007 Oct 9. [17924616 ]
  5. Carballa DM, Seoane S, Zacconi F, Perez X, Rumbo A, Alvarez-Diaz S, Larriba MJ, Perez-Fernandez R, Munoz A, Maestro M, Mourino A, Torneiro M: Synthesis and biological evaluation of 1alpha,25-dihydroxyvitamin D(3) analogues with a long side chain at C12 and short C17 side chains. J Med Chem. 2012 Oct 25;55(20):8642-56. doi: 10.1021/jm3008272. Epub 2012 Oct 4. [22989379 ]
  6. Chen B, Kawai M, Wu-Wong JR: Synthesis of VS-105: A novel and potent vitamin D receptor agonist with reduced hypercalcemic effects. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5949-52. doi: 10.1016/j.bmcl.2013.08.076. Epub 2013 Aug 24. [24035340 ]
  7. Lamblin M, Dabbas B, Spingarn R, Mendoza-Sanchez R, Wang TT, An BS, Huang DC, Kremer R, White JH, Gleason JL: Vitamin D receptor agonist/histone deacetylase inhibitor molecular hybrids. Bioorg Med Chem. 2010 Jun 1;18(11):4119-37. doi: 10.1016/j.bmc.2010.03.078. Epub 2010 Apr 7. [20452225 ]
  8. Adachi R, Honma Y, Masuno H, Kawana K, Shimomura I, Yamada S, Makishima M: Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. J Lipid Res. 2005 Jan;46(1):46-57. Epub 2004 Oct 16. [15489543 ]
General Function:
Iron ion binding
Specific Function:
Catalyzes the conversion of 25-hydroxyvitamin D3 (25(OH)D) to 1-alpha,25-dihydroxyvitamin D3 (1,25(OH)2D) plays an important role in normal bone growth, calcium metabolism, and tissue differentiation.
Gene Name:
CYP27B1
Uniprot ID:
O15528
Molecular Weight:
56503.475 Da
References
  1. Maehr H, Uskokovic MR, Reddy GS, Adorini L: Calcitriol derivatives with two different side chains at C-20. 24-hydroxy derivatives as metabolic products and molecular probes for VDR exploration. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):35-8. [15225743 ]
  2. Diesel B, Radermacher J, Bureik M, Bernhardt R, Seifert M, Reichrath J, Fischer U, Meese E: Vitamin D(3) metabolism in human glioblastoma multiforme: functionality of CYP27B1 splice variants, metabolism of calcidiol, and effect of calcitriol. Clin Cancer Res. 2005 Aug 1;11(15):5370-80. [16061850 ]
  3. Flynn G, Chung I, Yu WD, Romano M, Modzelewski RA, Johnson CS, Trump DL: Calcitriol (1,25-dihydroxycholecalciferol) selectively inhibits proliferation of freshly isolated tumor-derived endothelial cells and induces apoptosis. Oncology. 2006;70(6):447-57. Epub 2007 Jan 19. [17237620 ]
  4. Barrera D, Avila E, Hernandez G, Halhali A, Biruete B, Larrea F, Diaz L: Estradiol and progesterone synthesis in human placenta is stimulated by calcitriol. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):529-32. Epub 2006 Dec 23. [17257826 ]
  5. Andress DL: Vitamin D treatment in chronic kidney disease. Semin Dial. 2005 Jul-Aug;18(4):315-21. [16076355 ]
General Function:
Zinc ion binding
Specific Function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>10 uMNot AvailableBindingDB 50200182
References
  1. Nakamura M, Makishima M, Hashimoto Y: Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: selectivity switching by C/Si exchange. Bioorg Med Chem. 2013 Apr 1;21(7):1643-51. doi: 10.1016/j.bmc.2013.01.060. Epub 2013 Feb 6. [23462715 ]
General Function:
Vitamin transporter activity
Specific Function:
Involved in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5 alpha for neutrophils in inflammation and macrophage activation.
Gene Name:
GC
Uniprot ID:
P02774
Molecular Weight:
52963.025 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.024 uMNot AvailableBindingDB 50200182
References
  1. Sanchez-Abella L, Fernandez S, Verstuyf A, Verlinden L, Gotor V, Ferrero M: Synthesis, conformational analysis, and biological evaluation of 19-nor-vitamin D3 analogues with A-ring modifications. J Med Chem. 2009 Oct 8;52(19):6158-62. doi: 10.1021/jm900711d. [19739672 ]