Calcitroic acid

Calcitroic acid (1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D₃) is a major metabolite of 1α,25-dihydroxyvitamin D₃ (calcitriol).^[1] 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.^[1] 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.^[1] These pathways managed by calcitriol^[2] are thought to be inactivated^[3] through its hydroxylation by the enzyme CYP24A1, also called calcitriol 24-hydroxylase.^[4] Specifically, It is thought to be the major route to inactivate vitamin D metabolites.^[3] 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.^[5] However, the only scientifically known formation of calcitroic acid is through an oxidative reaction of the 1ɑ,25-dihydroxy vitamin D3. The positions of C24 and C23 undergo multiple oxidative reactions. Thus, causing the large and small side chains of 1ɑ,25-dihydroxy vitamin D3 to cleave off and form calcitroic acid.^[6]

Calcitroic acid

Names
IUPAC name (3R)-3-[(1R,3aR,4E,7aR)- 4-[(2Z)-2-[(3R,5R)-3,5- Dihydroxy-2-methylene-cyclohexylidene]ethylidene] -7a-methyl-2,3,3a,5,6,7-hexahydro-1H -inden-1-yl]butanoic acid
Identifiers
CAS Number	71204-89-2
3D model (JSmol)	Interactive image
ChemSpider	4947800
PubChem CID	6443842
CompTox Dashboard (EPA)	DTXSID60904030
InChI InChI=1/C23H34O4/c1-14(11-22(26)27)19-8-9-20-16(5-4-10-23(19,20)3)6-7-17-12-18(24)13-21(25)15(17)2/h6-7,14,18-21,24-25H,2,4-5,8-13H2,1,3H3,(H,26,27)/b16-6+,17-7-/t14-,18+,19-,20+,21-,23-/m1/s1 Key: MBLYZRMZFUWLOZ-FEUSBDLHBT
SMILES O=C(O)C[C@@H](C)[C@H]3CC[C@H]2C(=C\C=C1/C(=C)[C@H](O)C[C@@H](O)C1)\CCC[C@@]23C
Properties
Chemical formula	C23H34O4
Molar mass	374.514
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

The compound has been prepared in the laboratory.^[2]

Metabolism

Hydroxylation and further metabolism of calcitriol in the liver and the kidneys yields calcitroic acid, a water-soluble compound that is excreted in bile.^[1]

In vitro

In case where a higher concentration of this acid is used in vitro, studies determined that calcitroic acid binds to vitamin D receptor (VDR) and induces gene transcription.^[1]

Structure

There is an x-ray co-crystal structure of calcitroic acid that justifies that the calcitroic acid and vitamin D receptor have agonistic confirmation properties. Calcitroic acid has two side chains, the smaller side chain consists of a hydrogen bond with His333 and a single water molecule. In addition, the longer side chain consists of His333 and His423 interacting with 1,25(OH)2D3.^[7]