Dehydrocholic acid

Dehydrocholic Acid: A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Nomenclature

Dehydrocholic acid is a semisynthetic bile acid. Its systematic IUPAC name is (5beta)-3,7,12-Trioxocholan-24-oic Acid. Common synonyms include Triketocholanic Acid, Trioxocholate, Ketocholanic Acid, Sodium Dehydrocholate, and various trade or historical names including Decholin, Atrocholin, Cholan-HMB, and Chologon. Additional trade names historically used include Cholan DH, Dehycol, Bilidren, Acolen, Cholagon, Deidrocolico Vita, Didrojcolo, Hebile, Felacrinos, Dilabil, Bilostat, Oxycholin, and Procholon.

Its CAS number is 81-23-2, its molecular formula is C₂₄H₃₄O₅, and its molecular weight is 402.53 g/mol. The sodium salt form (sodium dehydrocholate) carries CAS number 145-41-5.

The NIH Medical Subject Headings (MeSH) identifier for dehydrocholic acid is D003685, and it carries the pharmacological action classification of Cholagogues and Choleretics.

Source and Natural Origin

Dehydrocholic acid is a synthetic bile acid, manufactured by the oxidation of cholic acid. This oxidation is accomplished using chromic acid. Naturally occurring bile acids, accounting for 95 percent of biliary bile acids, include cholic acid, chenodeoxycholic acid, and deoxycholic acid; minor bile acids include lithocholic acid and ursodeoxycholic acid. Dehydrocholic acid itself does not occur naturally in meaningful amounts — it is strictly described as a semisynthetic compound derived from cholic acid, which is abundant in animal bile.

Cholic acid, the starting material, exists in the bile of cattle, sheep, and pigs and is most abundant in bovine bile, with the bile acid content reaching 44 g in 1,000 ml of bovine bile.

Physical and Chemical Properties

Dehydrocholic acid, with the molecular formula C₂₄H₃₄O₅ and CAS Number 81-23-2, is a bile acid with a molecular weight of 402.52 g/mol. It is an oxidation product of cholic acid and exhibits moderate solubility and stability under physiological conditions. The compound is characterized by three keto groups at positions 3, 7, and 12 of the steroid ring system in place of the three hydroxyl groups found in cholic acid. As a semisynthetic cholate, it evokes the secretion of a bile of low specific gravity and is therefore called a hydrocholeretic acid, which by thinning the bile facilitates its flow.

Since dehydrocholic acid does not form micelles at physiologic concentrations, unlike typical bile acids, its mechanism of action differs fundamentally from that of conventional micellar bile acids.

Common Forms and Preparations

The NIH MeSH database lists dehydrocholic acid as available in multiple salt forms including lithium, magnesium, potassium, and sodium salts. It is used as a cholagogue, hydrocholeretic, diuretic, and as a diagnostic aid. Preparations have included oral tablets, oral solutions, and intravenous formulations of the sodium salt. In pharmaceutical practice, dehydrocholic acid at a dose of 500 mg has been combined with oral vitamin K (phytonadione) in patients with decreased bile secretion to ensure adequate fat-soluble vitamin absorption.

2. Historical Discovery and Early Use

Nineteenth-Century Chemistry

Hammarsten was the first to show that the three OH-groups of cholic acid are of secondary-alcoholic nature, and already in 1881 he succeeded in converting cholic acid into dehydrocholic acid, which contains six H-atoms less, through oxidation with chromium trioxide. This early synthesis predates any formal pharmacological investigation of the compound.

Early Twentieth-Century Therapeutic Use

First synthesized in the early 20th century, dehydrocholic acid was created through the oxidation of cholic acid, one of the primary bile acids produced in the liver. Its medicinal use quickly gained traction due to its choleretic properties — meaning it stimulates the production and flow of bile.

In the first half of the twentieth century, the only therapeutic use of bile acids was the administration of dehydrocholic acid (DHCA), which is an artificial 3,7,12-trioxo-cholic acid, in order to achieve choleresis in patients with liver disease (Hofmann & Hagey, 2008). This treatment is now largely abandoned.

During this time, bile acids were sold as liver tonics and laxatives, but there were no placebo-controlled studies showing efficacy. Indeed, bile acids were considered by the medical profession to have no useful therapeutic properties. The tri-oxo derivative of cholic acid (called "dehydrocholic acid") was known to induce bile flow in animals, and was occasionally used to stimulate bile flow in patients; but again there were no controlled studies showing efficacy in hepatobiliary disease.

The compound was first marketed in 1935, with Winternitz introducing the intravenous sodium salt form (Decholin) in 1931 for the measurement of arm-to-tongue circulation time. It was recommended not only for determination of circulation time, but for treatment of penicillin reactions, as a diuretic, and for its hydrocholeretic action in cholangitis and postoperative cholecystectomies.

Mid-Twentieth Century and OTC Status

Bile acids were sold as liver tonics and laxatives throughout this era. Dehydrocholic acid featured prominently in over-the-counter products in North America for several decades. The use of dehydrocholic acid in over-the-counter products has since been discontinued by Health Canada.

In the first half of the twentieth century, the only therapeutic use of bile acids was the administration of dehydrocholic acid (DHCA), in order to achieve choleresis in patients with liver disease. This treatment is now largely abandoned.

3. Key Constituents and Active Compounds

Structure and the Parent Bile Acid Relationship

Bile acids are detergents derived from cholesterol that function to solubilize dietary lipids, remove cholesterol from the body, and act as nutrient signaling molecules in numerous tissues, with functions in the liver and gut being the best understood.

Dehydrocholic acid as a single molecular entity is the active compound of interest. It has no complex phytochemical profile because it is a chemically defined, semisynthetic molecule rather than a botanical extract. Its structure features the characteristic tetracyclic steroid nucleus of the bile acid family, but with all three hydroxyl groups of cholic acid fully oxidized to ketone groups, making it a triketone.

Metabolites and Their Activity

In human subjects administered [24-¹⁴C]dehydrocholic acid intravenously, more than 80% of infused radioactivity was excreted rapidly in bile as glycine- and taurine-conjugated bile acids. Radioactive products were identified, after deconjugation, as partially or completely reduced derivatives of dehydrocholic acid. By mass spectrometry, as well as chromatography, the major metabolite (about 70%) was a dihydroxy monoketo bile acid (3α,7α-dihydroxy-12-keto-5β-cholanoic acid); a second metabolite (about 20%) was a monohydroxy diketo acid (3α-hydroxy-7,12-di-keto-5β-cholanoic acid); and about 10% of radioactivity was present as cholic acid.

Bile flow, expressed as the ratio of bile flow to bile acid excretion, was increased after dehydrocholic acid administration. It was speculated that the hydroxy keto metabolites are hydrocholeretics. The bile acids produced during DHCA infusion were composed of three hydroxy-oxo metabolites (83–93%) and cholic acid (6–14%). Very little DHCA was secreted unchanged (less than 2%).

The major site of metabolism is proposed to be the liver. The major metabolite accounting for 70% of total detectable metabolites is dihydroxymonoketo bile acid (3,7-dihydroxy-12-keto-5-cholanoic acid). About 20% of metabolites is monohydroxydiketoacid (3-hydroxy-7,12-keto-5-cholanoic acid) and about 10% is cholic acid.

4. Mechanisms of Action

Hydrocholeresis: The Primary Mechanism

Dehydrocholic acid acts as a hydrocholeretic, increasing bile output to clear increased bile acid load. As a semisynthetic cholate, it evokes the secretion of a bile of low specific gravity — hence its classification as a hydrocholeretic acid, which by thinning the bile facilitates its flow. The increase in bile flow evoked by bile acids is not a result of true cholepoiesis, since the augmented flow is only that necessary to secrete the increased load of bile acid imposed by that administered.

Dehydrocholic acid (DHC) is a synthetic non-micellar tri-keto bile acid shown to be a potent hydrocholeretic in animals and man. It is much more potent than micellar bile acids such as ursodeoxycholic acid (Actigall) by virtue of its non-micellar structure.

Effects on Biliary Lipid Composition

It is proposed that dehydrocholic acid induces choleresis, which is associated with biliary lipid secretion and reduced secretion of endogenous and/or exogenous biliary components. Dehydrocholic acid may decrease bile phospholipid secretion due to a lack of micelle formation by dehydrocholic acid-produced bile.

In rat studies, the secretions of all the endogenous biliary bile acids were diminished within 30–60 minutes of DHCA infusion. DHCA furthermore reduced the secretion of exogenous cholic acid when co-infused with DHCA.

The proportion of cholesterol to lecithin and bile acids did not change significantly after dehydrocholic acid administration. In vitro studies showed that the hydroxy keto metabolites dispersed lecithin poorly compared to cholate; however, mixtures of cholate and either metabolite had dispersant properties similar to those of cholate alone, provided the ratio of metabolite to cholate remained below a value characteristic for each metabolite.

Absorption and Pharmacokinetics

The duodenal route of experiments indicates that dehydrocholic acid is absorbed from the proximal small intestine. Administered dehydrocholic acid is excreted rapidly in bile as glycine- and taurine-conjugated bile acids. The major site of metabolism is proposed to be the liver.

Relationship to Cholesterol Metabolism Research

Researchers in France observed in 1953 that structures derived from dehydrocholic acid, phenylethyl acetic acid, and certain other disubstituted acetic acids exhibited hypocholesterolemic properties in rats and humans. Several years later, Thorp and Waring discovered clofibrate as an effective compound for lowering lipids in animal models, with minimal toxicity. This historical connection places dehydrocholic acid at the origin of the research lineage that eventually led to the development of fibrate lipid-lowering drugs, though dehydrocholic acid itself was not developed as a lipid-lowering agent.

5. Scientific Evidence by Area of Use

5.1 Choleresis and Bile Flow Stimulation

Animal and mechanistic studies: Dehydrocholic acid increases bile flow by 2.7-fold and decreases biliary levels of phospholipids, cholesterol, and bilirubin in conscious dogs when administered at a dose of 50 mg/kg. Dehydrocholic acid (1 µmol/min/0.1 kg) increases bile flow by 253% and decreases the secretion rate of phospholipids and cholesterol by 64 and 94%, respectively, in rats when infused intravenously at a dose of 2 µmol/min/0.1 kg.

Human studies: In a landmark study (Soloway, Hofmann et al., Journal of Clinical Investigation, 1973), [24-¹⁴C]dehydrocholic acid was synthesized from [24-¹⁴C]cholic acid, mixed with 200 mg of carrier, and administered intravenously to two patients with indwelling T-tubes designed to permit bile sampling without interruption of the enterohepatic circulation. More than 80% of infused radioactivity was excreted rapidly in bile as glycine- and taurine-conjugated bile acids. These experiments disclose a new metabolic pathway in man, provide further insight into the hydrocholeresis induced by keto bile acids, and indicate the striking change in pharmacologic and physical properties caused by replacement of hydroxyl by a keto substituent in the bile acid molecule.

Evidence strength: The choleretic effect of dehydrocholic acid in animals is well documented. The primary human study that characterized its metabolism and bile flow effects was a small investigation involving only two patients with T-tubes, limiting generalizability. The tri-oxo derivative of cholic acid was known to induce bile flow in animals and was occasionally used to stimulate bile flow in patients; but there were no controlled studies showing efficacy in hepatobiliary disease. Overall, while the mechanistic evidence is reasonably robust at the animal level, rigorous placebo-controlled human trials are absent.

5.2 Recurrent Cholangitis and Biliary Stasis

Biliary stasis leading to recurrent bouts of cholangitis in the absence of strictures is a rare but extremely vexing problem. Such patients often have dilated ducts in which sludge and stones form repeatedly despite endoscopic clearance and antibiotic treatment. Investigators hypothesized that stasis could be reduced and cholangitis lessened by continuous hydrocholeresis. Dehydrocholic acid (DHC) is a synthetic non-micellar tri-keto bile acid shown to be a potent hydrocholeretic in animals and man, and is much more potent than micellar bile acids such as ursodeoxycholic acid by virtue of its non-micellar structure.

An IRB-approved registry study was established to examine the effect of DHC in patients with recurrent cholangitis who did not have biliary obstruction due to strictures. Eleven patients treated for at least one year were included in the analysis. Eight men and three women, ranging in age from 36 to 75, had been treated for one to nine years. Six patients had a prior hepaticojejunostomy, and five patients had had cholecystectomy and biliary sphincterotomy. Two patients had been previously, unsuccessfully, treated with ursodeoxycholic acid. Comparing the year prior to and after initiation of DHC, there was a statistically significant decrease seen in inpatient hospital admissions (p < .05) and total number of episodes of cholangitis (p < .005).

Evidence strength: This 2019 HPB study represents one of the few prospective, IRB-registered clinical investigations specifically of dehydrocholic acid for an active patient population. However, its sample size of only 11 patients, the absence of a control arm, and the observational registry design substantially limit the strength of conclusions that can be drawn. The results are encouraging but preliminary.

5.3 Use as an Oral Laxative

Bile acids have effects on the intestine that are similar to those of other anionic surfactants and stimulant laxatives; they reduce net absorption of water and electrolytes and cause diarrhea if they escape ileal absorption. Dehydrocholic acid is considered safe and effective as an oral laxative when administered to adults in a dosage of 750 mg to 1.5 g daily in three doses. Dehydrocholate is also an effective hydrocholeretic in this dosage range.

Dehydrocholic acid is used as a gastrointestinal agent that stimulates the flow of bile into the duodenum (cholagogue) or stimulates the production of bile by the liver (choleretic). It is also used as a laxative to relieve constipation, as a diuretic, and as a diagnostic aid.

Evidence strength: The laxative application was historically accepted in regulatory frameworks in several countries and was part of the OTC monograph process in the United States. However, formal placebo-controlled modern trial data are lacking, and this use has largely been superseded by better-characterized agents.

5.4 Diagnostic Use: Circulation Time Measurement

There are two ways to measure human blood circulation time: the arm-to-lung and the arm-to-tongue method. The decholin (20% dehydrocholic acid) test is usually used to measure the arm-to-tongue circulation time. The following method was used: five ml of 20% decholin were injected into the right cubital vein over a 10-second period, and the latent time, the duration, the quality of the taste sensation, and the region of the tongue where the taste appeared were noted.

Since Winternitz introduced the use of Decholin in the measurement of circulation time in 1931, its usefulness has been both substantial and well documented. It was recommended not only for determination of circulation time, but for treatment of penicillin reactions, as a diuretic, and for its hydrocholeretic action in cholangitis and postoperative cholecystectomies.

Evidence strength: The diagnostic application (measuring arm-to-tongue circulation time) is well documented in historical clinical literature and represents a specific, procedural use that predates modern pharmacological standards. This application has been largely replaced by modern imaging and indicator techniques.

5.5 Post-Surgical Biliary Drainage

Dehydrocholic acid may be used after surgery to improve biliary drainage. Its hydrocholeretic properties make it theoretically useful in post-cholecystectomy situations where bile flow enhancement is desired, though rigorous clinical evidence from controlled trials is lacking.

5.6 Fat-Soluble Vitamin Absorption

Dehydrocholic acid aids the digestion of fats and increases absorption of fat-soluble vitamins. In patients with decreased bile secretion, dehydrocholic acid at 500 mg has been prescribed with each oral dose of phytonadione (vitamin K₁) to ensure adequate absorption. This application is based on the principle that bile acids are essential for the emulsification and micellar solubilization of lipophilic vitamins. However, direct clinical trial evidence specific to dehydrocholic acid's superiority over other bile preparations in this indication is not well-established in the modern literature.

5.7 Preliminary and Investigational Findings

Dehydrocholic acid (DHCA) was added to CV-1 (monkey kidney cell line), TT (a human oesophageal squamous carcinoma), and HT-29 (a human colon carcinoma) cells at 100 µM to afford approximately a 4-fold increase in CDX2 expression — CDX2 being a transcription factor associated with intestinal differentiation. This finding is in-vitro only and has no established clinical translation.

Dehydrocholic acid is a type of oral bile acid that, when supplemented along with a specific diet, has shown to alleviate symptoms of psoriasis in patients, especially in the acute form. It is used for short-term treatment and may have a theoretical risk of malignancy if used for a long period. This reference is from a handbook of natural medicine (2016); supporting clinical trial data for this specific indication are not available in indexed peer-reviewed literature.

6. Body Systems and Health Areas of Association

• Hepatobiliary system: The primary area of pharmacological interest. Dehydrocholic acid is used as a cholagogue, hydrocholeretic, diuretic, and as a diagnostic aid.
• Gastrointestinal system: Gastrointestinal agents that stimulate the flow of bile into the duodenum (cholagogues) or stimulate the production of bile by the liver (choleretics) include dehydrocholic acid.
• Fat and fat-soluble vitamin absorption: Dehydrocholic acid aids the digestion of fats and increases absorption of fat-soluble vitamins.
• Cardiovascular / Circulatory: Historical use as an intravenous agent for measuring arm-to-tongue circulation time, reflecting its rapid intravascular distribution kinetics.
• Renal/fluid: Dehydrocholic acid has been historically noted to possess mild diuretic properties, though the mechanistic basis is not fully characterized in modern literature.

7. Dosage Forms and Doses Reported in Sources

The usual daily dose of dehydrocholic acid may be 250–750 mg per day; dehydrocholic acid may be administered in doses of 250 mg ingested once or twice per day, usually before meals, or, for persons with sensitive gastrointestinal tracts, 125 mg two or three times per day before meals.

Dehydrocholic acid is considered safe and effective as an oral laxative when administered to adults in a dosage of 750 mg to 1.5 g daily in three doses. Dehydrocholate is also an effective hydrocholeretic in this dosage range.

The dose range used medicinally is 250 to 750 mg three times daily. The only contraindications listed are biliary obstruction and severe hepatitis (Martindale).

In the 2019 HPB clinical study of recurrent cholangitis, the investigators used dehydrocholic acid continuously in eleven patients followed for one to nine years, but the specific daily dose used in that registry was not stated in the available abstract.

For the diagnostic circulation-time application: Five ml of 20% decholin (sodium dehydrocholate) were injected into the right cubital vein over a 10-second period.

In animal research referenced in published work: 50 mg/kg was used in conscious dogs, and 1–2 µmol/min/0.1 kg was used as an intravenous infusion rate in rats.

8. Safety Considerations and Known Interactions

General Oral Safety

In general, bile acids and salts have only a minor toxic potential when given by mouth. In large doses they are likely to have the same effects as saponins; the main action is likely to be irritation of mucous membranes. Parenterally they are much more toxic and may cause haemolysis, a digitalis-like action on the heart, and effects on the central nervous system.

It is considered to be the least toxic of all the bile salts in man.

Gastrointestinal Adverse Effects

In the 2019 HPB clinical study, one patient experienced nausea, diarrhea, 8-pound weight loss, and pain in hands and feet on DHC. The symptoms abated after DHC was stopped and did not return when it was restarted. Other patients experienced only occasional diarrhea, which was controlled by dose adjustment. There were no other clinically significant side effects reported in that cohort.

Anaphylactic and Hypersensitivity Reactions (Parenteral Use)

An anaphylactic reaction to intravenous sodium dehydrocholate (Decholin) was reported in the peer-reviewed literature, published in the Annals of Internal Medicine, documenting that such serious hypersensitivity reactions, though rare, can occur with parenteral administration. Decholin is a sodium salt of dehydrocholic acid, an oxidative product of cholic acid, which is derived from the natural bile salts, and it is considered the least toxic of all the bile salts in man. This case underscores that rare but serious reactions are documented with the intravenous form.

Blood-Brain Barrier Effects (Animal Data)

In rats, sodium dehydrocholate disrupts the blood-brain barrier for a period of over three days. The clinical relevance of this finding for oral human use has not been established, but it indicates a potentially important safety consideration for parenteral forms.

Contraindications

The dose range used medicinally is 250–750 mg three times daily. The only contraindications listed in Martindale are biliary obstruction and severe hepatitis.

Dehydrocholic acid should not be used in individuals with known hypersensitivity to the drug or any of its components. It is contraindicated in patients with complete biliary obstruction, as increasing bile production in the absence of bile flow can exacerbate the condition. Caution is also advised in patients with severe liver disease or acute cholecystitis.

Drug Interactions

Drugs that alter liver enzyme activity, such as rifampin and phenobarbital, can impact the metabolism of dehydrocholic acid. These interactions can affect the drug's effectiveness and may require careful monitoring and dose adjustments.

Regulatory Status

The use of dehydrocholic acid in over-the-counter products has been discontinued by Health Canada. In the United States, the FDA maintained rulemaking history for OTC cholecystokinetic drug products referencing dehydrocholic acid. In current practice, this treatment is now largely abandoned in the context of mainstream hepatobiliary therapy, having been superseded by ursodeoxycholic acid and other approved agents.

9. Position in the Broader Bile Acid Pharmacology Landscape

Dehydrocholic acid-based treatment is now largely abandoned. Nowadays, the bile acid ursodeoxycholic acid (UDCA) is approved as a drug for the treatment of primary biliary cirrhosis.

Dehydrocholic acid is a compound that has been used in preparations along with cholic acid and has a strong choleretic effect. It is responsible for this choleretic effect more than cholic acid, and it has a weaker effect on the digestion and absorption of fats.

Dehydrocholic acid is used to improve biliary drainage in limited current clinical contexts, and small-scale clinical experience such as the 2019 HPB registry study suggests a continuing niche role for patients with recurrent cholangitis due to biliary stasis who have failed other treatments.

References

• NIH National Library of Medicine MeSH Browser — Dehydrocholic Acid (D003685)
• DrugBank — Dehydrocholic Acid (DB11622): Uses, Interactions, Mechanism of Action
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• ScienceDirect Topics — Dehydrocholic Acid: Overview (Pharmacology, Toxicology and Pharmaceutical Science)
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• Peters GA et al. An Anaphylactic Reaction to Sodium Dehydrocholate (Decholin). Annals of Internal Medicine. 1960;53(6):1228.
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• WHO JECFA — Cholic and desoxycholic acid and their salts. WHO Food Additives Series 5.
• US Patent 5,935,948 — Method of Treating and Preventing Gallstones (includes historical dehydrocholic acid dosage data).
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• Drugs.com Professional Monograph — Phytonadione (includes dehydrocholic acid co-administration note).
• Wikipedia — Dehydrocholic Acid (for cross-reference only; not a primary source)