Deoxycholic acid

Last updated
Deoxycholic acid
Deoxycholic acid.svg
Deoxycholic acid 3D ball.png
Sample of Sodium deoxycholate.jpg
Names
IUPAC name
3α,12α-Dihydroxy-5β-cholan-24-oic acid
Systematic IUPAC name
(4R)-4-[(1R,3aS,3bR,5aR,7R,9aS,9bS,11S,11aR)-7,11-Dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]pentanoic acid
Other names
Deoxycholate
Identifiers
3D model (JSmol)
3DMet
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.001.344 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C24H40O4/c1-14(4-9-22(27)28)18-7-8-19-17-6-5-15-12-16(25)10-11-23(15,2)20(17)13-21(26)24(18,19)3/h14-21,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15-,16-,17+,18-,19+,20+,21+,23+,24-/m1/s1 Yes check.svgY
    Key: KXGVEGMKQFWNSR-LLQZFEROSA-N Yes check.svgY
  • InChI=1/C24H40O4/c1-14(4-9-22(27)28)18-7-8-19-17-6-5-15-12-16(25)10-11-23(15,2)20(17)13-21(26)24(18,19)3/h14-21,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15-,16-,17+,18-,19+,20+,21+,23+,24-/m1/s1
    Key: KXGVEGMKQFWNSR-LLQZFEROBK
  • C[C@H](CCC(=O)O)[C@H]1CC[C@@H]2[C@@]1([C@H](C[C@H]3[C@H]2CC[C@H]4[C@@]3(CC[C@H](C4)O)C)O)C
Properties
C24H40O4
Molar mass 392.580 g·mol−1
Melting point 174–176 °C (345–349 °F; 447–449 K)
0.024% [1]
Acidity (pKa)6.58 [2]
-272.0·10−6 cm3/mol
Pharmacology
D11AX24 ( WHO )
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)
Deoxycholic acid
Clinical data
Trade names Kybella, Belkyra
AHFS/Drugs.com Monograph
License data
Identifiers
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.344 OOjs UI icon edit-ltr-progressive.svg

Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria metabolize chenodeoxycholic acid into the secondary bile acid lithocholic acid, and they metabolize cholic acid into deoxycholic acid. There are additional secondary bile acids, such as ursodeoxycholic acid. Deoxycholic acid is soluble in alcohol and acetic acid. When pure, it exists in a white to off-white crystalline powder form.

Contents

Deoxycholic acid is available as a generic medication in the United States as of April 2021, sold under the brand name Kybella among others. [8]

Applications

Deoxycholic acid has been used since its discovery in various fields of human medicine. In the human body deoxycholic acid is used in the emulsification of fats for absorption in the intestine. It has, in some countries (including Switzerland) been licensed as an emulsifier in food industry, [9] but it is no longer common. Outside the body it is used in experimental basis of cholagogues and is also in use to prevent and dissolve gallstones.[ citation needed ]

In research deoxycholic acid is used as a mild detergent for the isolation of membrane associated proteins. The critical micelle concentration for deoxycholic acid is approximately 2.4–4 mM. [10]

Sodium deoxycholate, the sodium salt of deoxycholic acid, is often used as a biological detergent to lyse cells and solubilise cellular and membrane components. [11] Sodium deoxycholate mixed with phosphatidylcholine, is used in mesotherapy injections to produce lipolysis, and has been used as an alternative to surgical excision in the treatment of lipomas. [12]

Deoxycholates and bile acid derivatives in general are actively being studied as structures for incorporation in nanotechnology. [13] They also have found application in microlithography as photoresistant components. [14]

In the United States, deoxycholic acid, under the brand name Kybella, is approved by the Food and Drug Administration for reducing moderate-to-severe fat below the chin. [6] [15] When injected into submental fat, deoxycholic acid helps destroy (adipocytes) fat cells, which are metabolized by the body over the course of several months. [15] Kybella is produced by Kythera Biopharmaceuticals. [16] [17]

Research in immunology

Its function as a detergent and isolating agent for membrane proteins also suits it for production of outer membrane protein (OMP) vaccines such as MenB, a Norwegian vaccine developed in the early 1990s. [18] The MeNZB vaccine was produced using the same method. [19]

Deoxycholic acid binds and activates the membrane enzyme NAPE-PLD, which catalyzes the release of the endogenous cannabinoid anandamide and other N-acylethanolamines. These bioactive signaling molecules play important roles in several physiological pathways including stress and pain response, appetite, and lifespan. [20]

Some publications point towards the effect of deoxycholic acid as an immunostimulant [21] [22] of the innate immune system, activating its main actors, the macrophages. According to these publications, a sufficient amount of deoxycholic acid in the human body would correspond with a good immune reaction of the non-specific immune system. Clinical studies conducted in the 1970s and 1980s confirm the expectation that deoxycholic acid is involved in the natural healing processes of local inflammations, [23] [24] different types of herpes, [25] [26] and possibly cancer. [27] [28]

Research in cancer

Deoxycholate and other secondary bile acids cause DNA damage. [29] Secondary bile acids increase intracellular production of reactive oxygen and reactive nitrogen species resulting in increased oxidative stress and DNA damage. [30] [31] As shown in the figure below, deoxycholate added to the diet of mice increased the level of 8-oxo-dG, an oxidative DNA damage, in the colonic epithelium of mice. When the level of deoxycholate-induced DNA damage is high, DNA repair enzymes that ordinarily reverse DNA damage may not be able to keep up.[ citation needed ]

DNA damage has frequently been proposed as a major cause of cancer. [32] [33] DNA damage can give rise to cancer by causing mutations.[ citation needed ]

When deoxycholate was added to the food of mice so that their feces contained deoxycholate at about the same level present in feces of human on a high fat diet, 45% to 56% of the mice developed colon cancer over the next 10 months, while none of the mice on a diet without deoxycholate developed cancer. [34] [35] Thus, exposure of the colon to deoxycholate may cause cancer in mice. However, this same study reported that, when chlorogenic acid was added to the diet alongside deoxycholate, only 18% of the mice developed colon cancer. Chlorogenic acid is a component of common foods and beverages; coffee contains an average of 53.8 mg chlorogenic acid per 100 ml. [36] Therefore, to consume the level of chlorogenic acid used in the study, a human on a "standard" 2000-calorie daily diet (416 g/d; 250g carbs, 100g protein, 66g fat) would need to consume roughly 55 mL of coffee each day, or just under 2 fluid ounces.

In humans, higher levels of colonic deoxycholate are associated with higher frequencies of colon cancer. As an example, the fecal deoxycholate concentrations in African Americans (who eat a relatively high fat diet) is more than five times higher than fecal deoxycholate of Native Africans in South Africa (who eat a low fat diet). [37] Male African Americans have a high incidence of colon cancer of 72 per 100,000, [38] while Native Africans in South Africa have a low incidence rate of colon cancer of less than 1 per 100,000, [39] a more than 72-fold difference in rates of colon cancer.

A prospective human study investigating the relationship between microbial metabolites and cancer found a strong correlation between circulating deoxycholic acid and colorectal cancer risk in women. [40]

Factors affecting deoxycholate levels

A number of factors, including diet, obesity, and exercise, affect the level of deoxycholate in the human colon. When humans were switched from their usual diet to a meat, egg and cheese based diet for five days, deoxycholate in their feces increased by factors of 2 to 10 fold. [41] Rats fed diets with 30% beef tallow (high fat) had almost 2-fold more deoxycholate in their feces than rats fed 5% beef tallow (low fat). [42] In the same study, adding the further dietary elements of curcumin or caffeic acid to the rats' high fat (30% beef tallow) diet reduced the deoxycholate in their feces to levels comparable to levels seen in the rats on a low fat diet. Curcumin is a component of the spice turmeric, and caffeic acid is a component high in some fruits and spices. [43] Caffeic acid is also a digestive break-down product of chlorogenic acid, high in coffee and some fruits and vegetables. [44]

Colonic epithelium from a mouse not undergoing colonic tumorigenesis (A), and a mouse that is undergoing colonic tumorigenesis (B). Cell nuclei are stained dark blue with hematoxylin (for nucleic acid) and immunostained brown for 8-oxo-dG. The level of 8-oxo-dG was graded in the nuclei of colonic crypt cells on a scale of 0-4. Mice not undergoing tumorigenesis had crypt 8-oxo-dG at levels 0 to 2 (panel A shows level 1) while mice progressing to colonic tumors had 8-oxo-dG in colonic crypts at levels 3 to 4 (panel B shows level 4) Tumorigenesis was induced by adding deoxycholate to the mouse diet to give a level of deoxycholate in the mouse colon similar to the level in the colon of humans on a high fat diet. The images were made from original photomicrographs. Colonic epithelium mouse without tumorigenesis (A) and with tumorigenesis (B). Brown shows 8-oxo-dG.jpg
Colonic epithelium from a mouse not undergoing colonic tumorigenesis (A), and a mouse that is undergoing colonic tumorigenesis (B). Cell nuclei are stained dark blue with hematoxylin (for nucleic acid) and immunostained brown for 8-oxo-dG. The level of 8-oxo-dG was graded in the nuclei of colonic crypt cells on a scale of 0–4. Mice not undergoing tumorigenesis had crypt 8-oxo-dG at levels 0 to 2 (panel A shows level 1) while mice progressing to colonic tumors had 8-oxo-dG in colonic crypts at levels 3 to 4 (panel B shows level 4) Tumorigenesis was induced by adding deoxycholate to the mouse diet to give a level of deoxycholate in the mouse colon similar to the level in the colon of humans on a high fat diet. The images were made from original photomicrographs.

In addition to fats, the type or amount of protein in the diet may also affect bile acid levels. Switching from a diet with protein provided by casein to a diet with protein provided by salmon protein hydrolysate led to as much as a 6-fold increase in levels of bile acids in the blood plasma of rats. [45] In humans, adding high protein to a high fat diet raised the level of deoxycholate in the plasma by almost 50%. [46]

Obesity has been linked to cancer, [47] and this link is in part through deoxycholate. [48] [49] [50] In obese people, the relative proportion of Firmicutes (Gram-positive bacteria) in gut microbiota is increased resulting in greater conversion of the non-genotoxic primary bile acid, cholic acid, to carcinogenic deoxycholate. [48]

Exercise decreases deoxycholate in the colon. Humans whose level of physical activity placed them in the top third had a 17% decrease in fecal bile acid concentration compared to those whose level of physical activity placed them in the lowest third. [51] Rats provided with an exercise wheel had a lower ratio of secondary bile acids to primary bile acids than sedentary rats in their feces. [52] There is a positive association of exercise and physical activity with cancer prevention, tolerance to cancer-directed therapies (radiation and chemotherapy), reduction in recurrence, and improvement in survival. [53]

Related Research Articles

<span class="mw-page-title-main">Carcinogen</span> Substance, radionuclide, or radiation directly involved in causing cancer

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

<span class="mw-page-title-main">Caffeic acid</span> Chemical compound

Caffeic acid is an organic compound that is classified as a hydroxycinnamic acid. This yellow solid consists of both phenolic and acrylic functional groups. It is found in all plants because it is an intermediate in the biosynthesis of lignin, one of the principal components of woody plant biomass and its residues.

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.

<i>Bacteroides</i> Genus of bacteria

Bacteroides is a genus of Gram-negative, obligate anaerobic bacteria. Bacteroides species are non endospore-forming bacilli, and may be either motile or nonmotile, depending on the species. The DNA base composition is 40–48% GC. Unusual in bacterial organisms, Bacteroides membranes contain sphingolipids. They also contain meso-diaminopimelic acid in their peptidoglycan layer.

<span class="mw-page-title-main">Oxoguanine glycosylase</span> DNA glycosylase enzyme

8-Oxoguanine glycosylase, also known as OGG1, is a DNA glycosylase enzyme that, in humans, is encoded by the OGG1 gene. It is involved in base excision repair. It is found in bacterial, archaeal and eukaryotic species.

<span class="mw-page-title-main">Free fatty acid receptor 3</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 3 protein is a G protein coupled receptor that in humans is encoded by the FFAR3 gene. GPRs reside on cell surfaces, bind specific signaling molecules, and thereby are activated to trigger certain functional responses in their parent cells. FFAR3 is a member of the free fatty acid receptor group of GPRs that includes FFAR1, FFAR2, and FFAR4. All of these FFARs are activated by fatty acids. FFAR3 and FFAR2 are activated by certain short-chain fatty acids (SC-FAs), i.e., fatty acids consisting of 2 to 6 carbon atoms whereas FFFAR1 and FFAR4 are activated by certain fatty acids that are 6 to more than 21 carbon atoms long. Hydroxycarboxylic acid receptor 2 is also activated by a SC-FA that activate FFAR3, i.e., butyric acid.

<span class="mw-page-title-main">Free fatty acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 2 (FFAR2), also termed G-protein coupled receptor 43 (GPR43), is a rhodopsin-like G-protein coupled receptor. It is coded by the FFAR2 gene. In humans, the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12. Like other GPCRs, FFAR2s reside on the surface membrane of cells and when bond to one of their activating ligands regulate the function of their parent cells. FFAR2 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes three other receptors which, like FFAR2, are activated by certain fatty acids: FFAR1, FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids whereas FFAR1 and FFAR4 are activated by long-chain fatty acids.

<span class="mw-page-title-main">Hydroxycarboxylic acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.

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3CH
2CO
2H) in its anionic "propionate" form (i.e., CH
3CH
2CO−
2) along with sodium cations (i.e., Na+) are co-transported from the extracellular fluid into a SMCT1-epxressing cell's cytoplasm. Monocarboxylate transporters (MCTs) are also transport proteins in the solute carrier family. They co-transport the anionic forms of various compounds into cells in association with proton cations (i.e. H+). Four of the 14 MCTs, i.e. SLC16A1 (i.e., MCT1), SLC16A7 (i.e., MCT22), SLC16A8 (i.e., MCT3), and SLC16A3 (i.e., MCT4), transport some of the same SC-FAs anions that the SMCTs transport into cells. SC-FAs do diffuse into cells independently of transport proteins but at the levels normally occurring in tissues far greater amounts of the SC-FAs are brought into cells that express a SC-FA transporter.

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References

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  2. ↑ Lide DR (1998). Handbook of Chemistry and Physics (87 ed.). Boca Raton, FL: CRC Press. p. 1287. ISBN   978-0-8493-0594-8.
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