:Chenodeoxycholic acid
{{Short description|One of the main bile acids}}
{{Use dmy dates|date=September 2020}}
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{{Chembox
| Verifiedfields = changed
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| verifiedrevid = 401952251
| Name = Chenodeoxycholic acid
| ImageFile = Chenodeoxycholic acid.svg
| ImageSize = 260
| ImageAlt = Skeletal formula of chenodeoxycholic acid
| ImageClass = skin-invert-image
| ImageFile1 = Chenodeoxycholic acid 3D ball.png
| ImageSize1 = 260
| ImageAlt1 = Ball-and-stick model of the chenodeoxycholic acid molecule
| IUPACName = 3α,7α-Dihydroxy-5β-cholan-24-oic acid
| SystematicName = (4R)-4-[(1R,3aS,3bR,4R,5aS,7R,9aS,9bS,11aR)-4,7-Dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]pentanoic acid
| OtherNames = Chenodiol
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 608
| UNII_Ref = {{fdacite|correct|FDA}}
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 240597
| UNII = 0GEI24LG0J
| InChI = 1/C24H40O4/c1-14(4-7-21(27)28)17-5-6-18-22-19(9-11-24(17,18)3)23(2)10-8-16(25)12-15(23)13-20(22)26/h14-20,22,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15+,16-,17-,18+,19+,20-,22+,23+,24-/m1/s1
| InChIKey = RUDATBOHQWOJDD-BSWAIDMHBF
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H40O4/c1-14(4-7-21(27)28)17-5-6-18-22-19(9-11-24(17,18)3)23(2)10-8-16(25)12-15(23)13-20(22)26/h14-20,22,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15+,16-,17-,18+,19+,20-,22+,23+,24-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RUDATBOHQWOJDD-BSWAIDMHSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 474-25-9
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 9728
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB06777
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 16755
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = C02528
| PubChem = 10133
| EC_number = 207-481-8
| SMILES = C[C@H](CCC(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@@H](C[C@H]4[C@@]3(CC[C@H](C4)O)C)O)C
}}
|Section2={{Chembox Properties
| Formula = C24H40O4
| MolarMass = 392.57 g/mol
| Density =
| MeltingPtC = 165 to 167
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| Section6 = {{Chembox Pharmacology
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| ATCCode_prefix = A05
| ATCCode_suffix = AA01
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| Legal_US = Rx-only
| Legal_US_comment = {{cite web | title=Chenodal- chenodiol tablet, film coated | website=DailyMed | date=6 December 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=769e0a3b-826d-4faf-9129-5eeb7ebe0b67 | access-date=22 February 2025}}{{cite web | title=Ctexli- chenodiol tablet, film coated | website=DailyMed | date=21 February 2025 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=015384e7-4ac5-4782-a309-e40cd1421c5b | access-date=17 April 2025}}
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| USAN = chenodiol
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Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the main bile acids.{{cite journal | vauthors = Russell DW | title = The enzymes, regulation, and genetics of bile acid synthesis | journal = Annual Review of Biochemistry | volume = 72 | pages = 137–174 | year = 2003 | pmid = 12543708 | doi = 10.1146/annurev.biochem.72.121801.161712 }}{{cite book|doi=10.1016/B978-0-12-416687-5.00011-7|chapter=Gastrointestinal Digestion and Absorption|title=Essentials of Medical Biochemistry|pages=137–164|year=2015| vauthors = Bhagavan N, Ha CE |isbn=9780124166875}}{{cite journal | vauthors = Dawson PA, Karpen SJ | title = Intestinal transport and metabolism of bile acids | journal = Journal of Lipid Research | volume = 56 | issue = 6 | pages = 1085–1099 | date = June 2015 | pmid = 25210150 | pmc = 4442867 | doi = 10.1194/jlr.R054114 | doi-access = free }} It was first isolated from the bile of the domestic goose, which gives it the "cheno" portion of its name (Greek: χήν = goose).{{cite journal | vauthors = Carey MC | title = Editorial: Cheno and urso: what the goose and the bear have in common | journal = The New England Journal of Medicine | volume = 293 | issue = 24 | pages = 1255–1257 | date = December 1975 | pmid = 1186807 | doi = 10.1056/NEJM197512112932412 }}
Structure
Chenodeoxycholic acid and cholic acid are the two primary bile acids in humans. Chenodeoxycholic acid has two hydroxyl groups and is modified with the addition of another hydroxyl group to produce cholic acid. Some other mammals have muricholic acid or deoxycholic acid rather than chenodeoxycholic acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C.{{citation needed|date=September 2020}}
Biosynthesis and function
Chenodeoxycholic acid is synthesized in the liver from cholesterol via several enzymatic steps. Like other bile acids, it can be conjugated with taurine or glycine, forming taurochenodeoxycholate or glycochenodeoxycholate. Conjugation results in a lower pKa. This results in the conjugated bile acids being ionized at the usual pH in the intestine, and staying in the gastrointestinal tract until reaching the ileum to be reabsorbed.
CDCA and other bile acids are surfactants forming micelles with fats, which facilitate lipid digestion. After absorption, they are taken up by the liver and resecreted, so undergoing an enterohepatic circulation. Unabsorbed CDCA can be metabolised by bacteria in the colon to form the secondary bile acid, lithocholic acid or the epimer, ursodeoxycholic acid.
CDCA is the most potent natural bile acid at stimulating the nuclear bile acid receptor, farnesoid X receptor (FXR).{{cite journal | vauthors = Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM | title = Bile acids: natural ligands for an orphan nuclear receptor | journal = Science | volume = 284 | issue = 5418 | pages = 1365–1368 | date = May 1999 | pmid = 10334993 | doi = 10.1126/science.284.5418.1365 | bibcode = 1999Sci...284.1365P }} The transcription of many genes is activated by FXR, including those encoding FGF19 and small heterodimer partner.{{cite book | vauthors = Shin DJ, Wang L |title=Bile Acid-Activated Receptors: A Review on FXR and Other Nuclear Receptors. |series=Handbook of Experimental Pharmacology |date=2019 |volume=256 |pages=51–72 |doi=10.1007/164_2019_236 |pmid=31230143|isbn=978-3-030-22004-4 |s2cid=195327087 }}
Therapeutic applications
In the European Union, chenodeoxycholic acid is indicated for the treatment of inborn errors of primary bile acid synthesis due to sterol 27 hydroxylase deficiency (presenting as cerebrotendinous xanthomatosis).
In the United States, chenodeoxycholic acid is indicated for people with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. It is also indicated for the treatment of cerebrotendinous xanthomatosis in adults.
=Gallstones=
Chenodeoxycholic acid has been used as medical therapy to dissolve gallstones.{{cite journal | vauthors = Thistle JL, Hofmann AF | title = Efficacy and specificity of chenodeoxycholic acid therapy for dissolving gallstones | journal = The New England Journal of Medicine | volume = 289 | issue = 13 | pages = 655–659 | date = September 1973 | pmid = 4580472 | doi = 10.1056/NEJM197309272891303 }}{{cite journal | vauthors = Hofmann AF | title = Medical dissolution of gallstones by oral bile acid therapy | journal = American Journal of Surgery | volume = 158 | issue = 3 | pages = 198–204 | date = September 1989 | pmid = 2672842 | doi = 10.1016/0002-9610(89)90252-3 }} Medical therapy with oral bile acids has been used in patients who have small cholesterol stones, and for patients with larger cholesterol gallstones who are unable or reluctant to have surgery. CDCA treatment can cause diarrhea, mild reversible hepatic injury, and a small increase in the plasma cholesterol level.
=Cerebrotendinous xanthomatosis=
Chenodeoxycholic acid can be used in the treatment of cerebrotendinous xanthomatosis.{{cite journal | vauthors = Berginer VM, Salen G, Shefer S | title = Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid | journal = The New England Journal of Medicine | volume = 311 | issue = 26 | pages = 1649–1652 | date = December 1984 | pmid = 6504105 | doi = 10.1056/NEJM198412273112601 }}
In March 2025, chenodeoxycholic acid (Ctexli) was approved in the United States for the treatment of cerebrotendinous xanthomatosis in adults.{{cite press release | title=FDA Approves First Treatment for Cerebrotendinous Xanthomatosis, a Rare Lipid Storage Disease | website=U.S. Food and Drug Administration (FDA) | date=21 February 2025 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-cerebrotendinous-xanthomatosis-rare-lipid-storage-disease | access-date=7 March 2025}} {{PD-notice}} Ctexli is the first medication approved by the US Food and Drug Administration (FDA) to treat cerebrotendinous xanthomatosis, a very rare lipid storage disease.
The most common side effects of chenodeoxycholic acid are diarrhea, headache, abdominal pain, constipation, hypertension, muscular weakness and upper respiratory tract infection.
The efficacy of chenodeoxycholic acid for the treatment of people with cerebrotendinous xanthomatosis was evaluated in a double-blind, placebo controlled, randomized crossover withdrawal trial. The 24-week trial demonstrated that treatment with chenodeoxycholic acid, 250 milligrams three times per day, resulted in significant reduction in plasma cholestanol and urine 23S-pentol (cholesterol metabolites that are markedly increased in people with cerebrotendinous xanthomatosis) compared to placebo treatment.
The US prescribing information for chenodeoxycholic acid includes a warning for liver toxicity in all people with increased risk for liver damage in people with pre-existing liver disease or bile duct abnormalities.
The FDA granted the application for chenodeoxycholic acid priority review, fast track, and orphan drug designations. The approval of Ctexli was granted to Mirum Pharmaceuticals Inc.
=Other=
Chenodeoxycholic acid has been used in several other conditions.{{cite journal | vauthors = Broughton G | title = Chenodeoxycholate: the bile acid. The drug. a review | journal = The American Journal of the Medical Sciences | volume = 307 | issue = 1 | pages = 54–63 | date = January 1994 | pmid = 8291509 | doi = 10.1097/00000441-199401000-00011 }} As diarrhea is frequent when CDCA is used in gallstone dissolution, it has been studied as a possible treatment for constipation and has been shown to accelerate colonic transit and improve bowel function.{{cite journal | vauthors = Rao AS, Wong BS, Camilleri M, Odunsi-Shiyanbade ST, McKinzie S, Ryks M, Burton D, Carlson P, Lamsam J, Singh R, Zinsmeister AR | title = Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis | journal = Gastroenterology | volume = 139 | issue = 5 | pages = 1549–58, 1558.e1 | date = November 2010 | pmid = 20691689 | pmc = 3189402 | doi = 10.1053/j.gastro.2010.07.052 }}
The Australian biotechnology company Giaconda has tested a treatment for hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.{{cite press release |author=Giaconda|date=8 July 2008|title=Giaconda Suspends Hepaconda Phase II Trial to Carry Out Dose Ranging|url=http://www.fiercebiotech.com/press-releases/giaconda-suspends-hepaconda-phase-ii-trial-carry-out-dose-ranging|work=Fierce Biotech|location=Sydney, Australia|access-date=5 April 2014|archive-date=7 April 2014|archive-url=https://web.archive.org/web/20140407084044/http://www.fiercebiotech.com/press-releases/giaconda-suspends-hepaconda-phase-ii-trial-carry-out-dose-ranging|url-status=live}}
Cancer
An updated systematic review and meta-analysis on the relationship of fecal bile acid concentrations to the development and progression of colorectal cancer was reported.{{cite journal |vauthors=Yang S, Wang Y, Sheng L, Cui W, Ma C |title=The effect of fecal bile acids on the incidence and risk-stratification of colorectal cancer: an updated systematic review and meta-analysis |journal=Sci Rep |volume=15 |issue=1 |pages=740 |date=January 2025 |pmid=39753873 |pmc=11698987 |doi=10.1038/s41598-024-84801-6 |url=}} Higher fecal concentrations of chenodeoxycholic acid were found to be associated with a higher risk and higher incidence of colorectal cancer. Bile acids may act as carcinogens in the gastrointestinal tract.{{cite journal |vauthors=Bernstein H, Bernstein C |title=Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system |journal=Exp Biol Med (Maywood) |volume=248 |issue=1 |pages=79–89 |date=January 2023 |pmid=36408538 |pmc=9989147 |doi=10.1177/15353702221131858 |url=}}
References
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{{Bile and liver therapy}}
{{FXR and LXR modulators}}
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