Glycyrrhetinic acid
Encyclopedia
Glycyrrhetinic acid is a pentacyclic triterpenoid
derivative of the beta-amyrin type obtained from the hydrolysis
of glycyrrhizic acid, which was obtained from the herb liquorice. It is used in flavoring and it masks the bitter taste of drugs like aloe
and quinine
. It is effective in the treatment of peptic ulcer
and also has expectorant
(antitussive) properties. It has some additional pharmacological properties including antiviral, antifungal, antiprotozoal, and antibacterial activities.
s (15-hydroxyprostaglandin dehydrogenase
and delta-13-prostaglandin) that metabolize the prostaglandin
s PGE-2 and PGF-2α to their respective 15-keto-13,14-dihydro metabolite
s which are inactive. This causes an increased level of prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion but stimulate pancreatic
secretion and mucous secretion in the intestines and markedly increase intestinal motility. They also cause cell proliferation in the stomach
. The effect on gastric acid
secretion, promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcer.
PGF-2α stimulates activity of the uterus during pregnancy and can cause abortion, therefore, licorice should not be taken during pregnancy.
The structure of glycyrrhetinic acid is similar to that of cortisone
. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory
action.
3-β-D-(monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of active cortisol
to inactive cortisone
in the kidneys. This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase
. As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone
and increases sodium
reabsorption) that work on ENaC channels in the collecting duct. Hypertension
develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin
and low aldosterone
blood level. The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure
and inhibition of the renin-angiotensin-aldosterone system. Therefore licorice should not be given to patients with a known history of hypertension.
(R) is a hydroxyl
group. Research in 2005 demonstrated that with a proper functional group a very effective glycyrrhetinic artificial sweetener can be obtained. When R is an anionic NHCO(CH2)CO2K side chain
, the sweetening effect is found to 1200 times that of sugar
(human sensory panel data). A shorter or longer spacer reduces the sweetening effect. One explanation is that the taste bud
cell receptor
has 1.3 nanometers (13 angstrom
s) available for docking with the sweetener molecule. In addition the sweetener molecule requires three proton
donor positions of which two reside at the extremities to be able to interact efficiently with the receptor cavity.
A synthetic analog, carbenoxolone
, was developed in Britain. Both glycyrrhetinic acid and carbenoxolone have a modulatory effect on neural signaling through gap junction
channels.
Acetoxolone
, the acetyl
derivative of glycyrrhetinic acid, is a drug used in the treatment of peptic ulcer
and gastroesophageal reflux disease
.
Triterpenoid
Triterpenoids are terpenoid derviatives of triterpene molecules.They may have useful anti-cancer properties.Notable examples*Betulinic acid, possible anti-cancer drug*Bardoxolone methyl, inflammation modulator*Triterpenoid saponins...
derivative of the beta-amyrin type obtained from the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of glycyrrhizic acid, which was obtained from the herb liquorice. It is used in flavoring and it masks the bitter taste of drugs like aloe
Aloe
Aloe , also Aloë, is a genus containing about 500 species of flowering succulent plants. The most common and well known of these is Aloe vera, or "true aloe"....
and quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
. It is effective in the treatment of peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
and also has expectorant
Cough medicine
A cough medicine is a medicinal drug used in an attempt to treat coughing and related conditions. For dry coughs, treatment with cough suppressants may be attempted to suppress the body's urge to cough...
(antitussive) properties. It has some additional pharmacological properties including antiviral, antifungal, antiprotozoal, and antibacterial activities.
Mechanism of action
Glycyrrhetinic acid inhibits the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s (15-hydroxyprostaglandin dehydrogenase
15-hydroxyprostaglandin dehydrogenase (NAD+)
In enzymology, a 15-hydroxyprostaglandin dehydrogenase is an enzyme that catalyzes the chemical reaction--11alpha,15-dihydroxy-9-oxoprost-13-enoate + NAD+ \rightleftharpoons -11alpha-hydroxy-9,15-dioxoprost-13-enoate + NADH + H+...
and delta-13-prostaglandin) that metabolize the prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s PGE-2 and PGF-2α to their respective 15-keto-13,14-dihydro metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s which are inactive. This causes an increased level of prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion but stimulate pancreatic
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
secretion and mucous secretion in the intestines and markedly increase intestinal motility. They also cause cell proliferation in the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
. The effect on gastric acid
Gastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
secretion, promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcer.
PGF-2α stimulates activity of the uterus during pregnancy and can cause abortion, therefore, licorice should not be taken during pregnancy.
The structure of glycyrrhetinic acid is similar to that of cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
action.
3-β-D-(monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of active cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
to inactive cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
in the kidneys. This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase
11Beta Hydroxysteroid dehydrogenase
11β-Hydroxysteroid dehydrogenase is the name of a family of enzymes that catalyze the conversion of inert 11 keto-products to active cortisol, or vice versa, thus regulating the access of glucocorticoids to the steroid receptors.-Function:Cortisol, a glucocorticoid, binds the glucocorticoid...
. As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
and increases sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
reabsorption) that work on ENaC channels in the collecting duct. Hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
and low aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
blood level. The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and inhibition of the renin-angiotensin-aldosterone system. Therefore licorice should not be given to patients with a known history of hypertension.
Derivatives
In glycyrrhetinic acid, the functional groupFunctional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
(R) is a hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group. Research in 2005 demonstrated that with a proper functional group a very effective glycyrrhetinic artificial sweetener can be obtained. When R is an anionic NHCO(CH2)CO2K side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
, the sweetening effect is found to 1200 times that of sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
(human sensory panel data). A shorter or longer spacer reduces the sweetening effect. One explanation is that the taste bud
Taste bud
Taste buds contain the receptors for taste. They are located around the small structures on the upper surface of the tongue, soft palate, upper esophagus and epiglottis, which are called papillae. These structures are involved in detecting the five elements of taste perception: salty, sour,...
cell receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
has 1.3 nanometers (13 angstrom
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
s) available for docking with the sweetener molecule. In addition the sweetener molecule requires three proton
Hydrogen ion
Hydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes.Depending on the charge of the ion, two different classes can be distinguished: positively charged ions and negatively charged ions....
donor positions of which two reside at the extremities to be able to interact efficiently with the receptor cavity.
A synthetic analog, carbenoxolone
Carbenoxolone
Carbenoxolone, a synthetic derivative of glycyrrhetinic acid, is a licensed drug for oesophageal ulceration and inflammation. Other uses include treatment of oral and perioral lesions....
, was developed in Britain. Both glycyrrhetinic acid and carbenoxolone have a modulatory effect on neural signaling through gap junction
Gap junction
A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells....
channels.
Acetoxolone
Acetoxolone
Acetoxolone is a drug used for peptic ulcer and gastroesophageal reflux disease. It is an acetyl derivative of glycyrrhetinic acid....
, the acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
derivative of glycyrrhetinic acid, is a drug used in the treatment of peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
and gastroesophageal reflux disease
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
.