Enoxolone (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, BAN; also known as glycyrrhetinic acid or glycyrrhetic acid) is a pentacyclic

triterpenoid Triterpenes are a class of chemical compounds composed of three terpene units with the molecular formula C30H48; they may also be thought of as consisting of six isoprene units. Animals, plants and fungi all produce triterpenes, including squal ...

derivative of the

beta-amyrin The amyrins are three closely related natural chemical compounds of the triterpene class. They are designated α-amyrin (ursane skeleton), β-amyrin (oleanane skeleton) and δ-amyrin. Each is a pentacyclic triterpenol with the chemical formula C ...

type obtained from the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

glycyrrhizic acid Glycyrrhizin (or glycyrrhizic acid or glycyrrhizinic acid) is the chief sweet-tasting constituent of ''Glycyrrhiza glabra'' (liquorice) root. Structurally, it is a saponin used as an emulsifier and gel-forming agent in foodstuffs and cosmetics. ...

, which was obtained from the herb

liquorice Liquorice (British English) or licorice (American English) ( ; also ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring can be extracted. The liqu ...

. It is used in

flavoring A flavoring (or flavouring), also known as flavor (or flavour) or flavorant, is a food additive used to improve the taste or smell of food. It changes the perceptual impression of food as determined primarily by the chemoreceptors of the gusta ...

and it masks the bitter taste of drugs like

aloe ''Aloe'' (; also written ''Aloë'') is a genus containing over 650 species of flowering succulent plants.WFO (2022): Aloe L. Published on the Internet;http://www.worldfloraonline.org/taxon/wfo-4000001341. Accessed on: 06 Nov 2022 The most wid ...

and

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...

. It is effective in the treatment of

peptic ulcer Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...

and also has

expectorant Mucoactive agents are a class of chemical agents that aid in the clearance of mucus or sputum from the upper and lower airways, including the lungs, bronchi, and trachea. Mucoactive drugs include expectorants, mucolytics, mucoregulators, and muco ...

(antitussive) properties. It has some additional pharmacological properties with possible antiviral, antifungal, antiprotozoal, and antibacterial activities.

Mechanism of action

Glycyrrhetinic acid inhibits the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s ( 15-hydroxyprostaglandin dehydrogenase and delta-13-prostaglandin) that metabolize the

prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...

s PGE-2 and PGF-2α to their respective, inactive 15-keto-13,14-dihydro

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s. This increases prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion, stimulate

pancreatic The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

secretion and mucous secretion in the

intestines The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...

, and markedly increase intestinal motility. They also cause cell proliferation in the

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

. The effect on

gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...

secretion, and promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcers. Licorice should not be taken during pregnancy, because PGF-2α stimulates activity of the uterus during pregnancy and can cause abortion. The structure of glycyrrhetinic acid is similar to that of

cortisone Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug; it is not synthesized in the adrenal glands. Cortisol is converted by the action of the enzy ...

. Both molecules are flat and similar at positions 3 and 11. This might be the basis for licorice's

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

action. 3-β-D-(Monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of 'active'

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

to 'inactive'

in the

kidneys The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

. This occurs via inhibition of the enzyme 11-β-hydroxysteroid dehydrogenase. As a result, cortisol levels become high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

and increases

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

reabsorption) that work on ENaC channels in the collecting duct.

Hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

develops due to this mechanism of sodium retention. People often have

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

with a low

renin Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

and low

blood level. The increased amounts of cortisol binds to the unprotected, nonspecific mineralocorticoid receptors and induce sodium and fluid retention,

hypokalaemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnor ...

, and inhibition of the renin-angiotensin-aldosterone system. Therefore, licorice should not be given to patients with a known history of hypertension in doses sufficient to inhibit 11-β-hydroxysteroid dehydrogenase.

Derivatives

In glycyrrhetinic acid, the

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...

(R) is a

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

group. Research in 2005 demonstrated that with a proper functional group a very effective glycyrrhetinic

artificial sweetener A sugar substitute is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie () or low-calorie sweetener. Artificial sweeteners may be d ...

can be obtained. When R is an

anionic An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

NHCO(CH₂)CO₂K

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 the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a l ...

, the sweetening effect is found to be 1200 times that of

sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...

(human sensory panel data). A shorter or longer spacer reduces the sweetening effect. One explanation is that the

taste bud Taste buds contain the taste receptor cells, which are also known as gustatory cells. The taste receptors are located around the small structures known as lingual papillae, papillae found on the upper surface of the tongue, soft palate, upper e ...

cell

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

has 1.3

nanometer 330px, Different lengths as in respect to the molecular scale. The nanometre (international spelling as used by the International Bureau of Weights and Measures; SI symbol: nm) or nanometer (American and British English spelling differences#-re ...

s (13

angstrom The angstromEntry "angstrom" in the Oxford online dictionary. Retrieved on 2019-03-02 from https://en.oxforddictionaries.com/definition/angstrom.Entry "angstrom" in the Merriam-Webster online dictionary. Retrieved on 2019-03-02 from https://www.m ...

s) available for docking with the sweetener molecule. In addition, the sweetener molecule requires three

proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...

donor positions, of which two reside at the extremities, to be able to interact efficiently with the receptor cavity. A synthetic analog,

carbenoxolone Carbenoxolone (CBX) is a glycyrrhetinic acid derivative with a steroid-like structure, similar to substances found in the root of the licorice plant. Carbenoxolone is used for the treatment of peptic, esophageal and oral ulceration and inflammat ...

, was developed in Britain. Both glycyrrhetinic acid and carbenoxolone have a modulatory effect on neural signaling through

gap junction Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

channels. Acetoxolone, the

acetyl In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...

derivative of glycyrrhetinic acid, is a drug used in the treatment of

and

gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

SARS-CoV and COVID-19 Therapeutic

It has an anti-inflammatory effect. Highly effective antiviral, effective against

influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...

, SARS CoV and SARS CoV-2 (

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...

) viruses. Excessive consumption lowers

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...

levels in the blood, which in turn raises blood pressure as well as lowers blood sugar levels. Its side effects can be offset by potassium and carbohydrate supplementation, and can be offset by consuming

banana A banana is an elongated, edible fruit – botanically a berry – produced by several kinds of large herbaceous flowering plants in the genus ''Musa''. In some countries, bananas used for cooking may be called "plantains", distinguis ...

s naturally.

References

External links

* {{Saponins 11β-Hydroxysteroid dehydrogenase inhibitors Sugar substitutes Carboxylic acids Flavors Triterpenes Cyclohexanols Enones Dermatologic drugs

Mechanism of action

Derivatives

SARS-CoV and COVID-19 Therapeutic

See also

References

Further reading

External links