Some important phytochemicals from Yashtimadhu-Licorice (Glycyrrhiza glabra)

Some important phytochemicals from
Yashtimadhu-Licorice (Glycyrrhiza glabra)
By

Dr. Hemant Vinze  (M. S.)

Introduction
Yashtimadhu-licorice (Glycyrrhiza glabra) is used mainly for the treatment of pharyngitis, laryngitis, respiratory diseases such as bronchitis; GI conditions such as gastritis (hyperacidity) and in many polyherbal medicinal formulations. Yashtimadhu-licorice (Glycyrrhiza glabra), in fact, exhibits pleotropic pharmacological activity. Needless to say this is due to many pharmacologically active phytochemicals contained in it. In this article I present a few important pharmacologically active phytochemicals from Yashtimadhu-licorice (Glycyrrhiza glabra).  

Glabrol
Molecular formula: C25H28O4
Structural formula:

  

Glabrol is an acyl-coenzyme A. It is isolated from the roots of yashtimadhu-licorice (Glycyrrhiza glabra). Cholesterol acyltransferase esterifies free cholesterol in the liver and the intestine. Accumulation of these esters produce atherosclerosis. By inhibiting cholesterol acyltransferase glabrol prevents the development of hypercholesterolemia and atherosclerosis. Therefore glabrol can be used for the prevention and treatment of obesity and type 2 diabetes and atherosclerosis. [1], [2]

By binding to gamma aminobutyric acid (GABA) receptors glabrol exhibit hypnotic effect. When administered at 5, 10, 25 and 50 mg/kg body weight glabrol increased the duration of sleep and decreased sleep latency in a dose-dependent manner.   The hypnotic effect of glabrol was blocked by flumazepil, a selective benzodiazepine receptor antagonist.  [3]   

Glabrolide:
Molecular formula: C30H44O4
Structural formula:




Glabrolide was isolated from yashtimadhu-licorice (Glycyrrhiza glabra) by Shen et al.
223-acetoxyglycyrrhetic acid is the parent compound of glabrolide. The ' trivial' name (that is the name not recognized according to the rules of any formal system of chemical nomenclature) "glycyrrhetol" was used in the English abstracts for glabrolide.  

Glabrolide belongs to 'triterpenoids' group of chemicals.  

Glabrolide is practically insoluble in water and weak acidic solvents. 

Glabrolide is found in many herbs and spices. Isolated in pure form glabrolide does not actively exert pharmacological action but acts as a catalyst to other phytochemicals found in yashtimadhu-licorice (Glycyrrhiza glabra). 
Glabrolide can be found in yashtimadhu-licorice (Glycyrrhiza glabra), many herbs and spices. Glabrolide is a biomarker for the consumption of these food products. [4], [5], [6]  

Isoglabrolide:
Molecular formula: C30H44O4
Structural formula:





Isoglabrolide is a member of the class of compounds known as triterpenoids. Isoglabrolide isinsoluble in water and weak acidic solvents. It is found in yashtimadhu-licorice (Glycyrrhiza glabra), many herbs, tea and spices. Isoglabrolide is a biomarker for consumption of these food products. [7], [8]

Glycyrrhetol 
Molecular formula: C30H48O3
Structural formula:





Glycyrrhetol is a member compounds known as triterpenoids. Glycyrrhetol is insoluble in water and weak acidic solvents. It is found in yashtimadhu-licorice (Glycyrrhiza glabra), tea and spices.   Glycyrrhetol is a biomarker for consumption of these food products.  [9] 

Flavones/Flavonoids

The flavonoid constituents in yashtimadhu-licorice (Glycyrrhiza glabra) mainly include flavones, flavonals, isoflavones, chalcones, bihydroflavones and bihydrochalcones. They show antioxidant, antibacterial, antiviral, antitumor activities. 

They inhibit HIV infection.   [10]

Till 1994, eight saponins, seven flavonoid glycosides and eleven flavonoids had been isolated from licorice. Later five new flavonoid compounds isolated from yashtimadhu-licorice (Glycyrrhiza glabra) were: glucoliquitrin apioside,                     phenyllicoflavone A (a flavonone bisdesmoside), shinflavone (a bisflavone), shinpterocarpin (a phenylated pyranoflavonone),   and 1-methoxyphaseollin, (both pyranopterocarpans).  [11] 

A new flavonoid compound isolated from yashtimadhu-licorice (Glycyrrhiza glabra) named licoagrodione was found to show antimicrobial activity indicated by disc diffusion method. [12]

Triterpenoids/ Triterpenes

Triterpenes are a class of chemical compounds composed of three terpene units with the molecular formula C30H48. These may be broadly divided according to the number of rings present.
The triterpenoids isolated recently from yashtimadhu-licorice (Glycyrrhiza glabra) exhibited a broad spectrum anti-viral   activity.[13]

Isoliquiritigenin
Molecular formula: C15H12O4
Structural formula:



Isoliquiritigenin is a phenolic compound found in yashtimadhu-licorice (Glycyrrhiza glabra).  
     
The enzyme isoliquitrigenin 2-O-methyltransferase further transforms isoliquitrigenin into 2-O-methylisoliquiritigenin. 

Isoliquiritigenin is a potent benzodiapin receptor modulator.

Isoliquiritigenin is under trial for the treatment for cocaine addiction and various cancers. [14]

Isoliquiritigenin exhibits anti-inflammatory, anti-oxidant, immunoregulatory, anti-microbial, hepatoprotective, cardioprotective and anticancer activities. However further studies are needed to verify the target organ toxicity. [15]

A study showed that isoliquiritigenin inhibited antral growth and altered estradiol, testosterone and progesterone levels. These data indicate that exposure to isoliquiritigenin inhibits growth and disrupts steroid production in antral follicles. [16]

Isoliquiritin
Molecular formula: C21H22O9
Structural formula:



Isoliquiritin is a member of the class of compounds known as flavonoid-o-glycosides. Isoliquiritin   is practically insoluble in water and weakly acidic solvents. Isoliquiritin can be found in yashtimadhu-licorice (Glycyrrhiza glabra), fruits and tea. This makes isoliquiritin a potential biomarker for the consumption of these food products.  [17], [18]  

Isoliquiritin flavonoid possesses anti-inflammatory, anti-oxidant, immunoregulatory and antidepressant properties. The mechanisms of neuroprotective and antidepressant activities are however unclear. The results of some studies showed that pretreatment of PC12 cells with isoliqutritin significantly prevented corticosterone-induced cell apoptosis, increased the activity of superoxidedismutase (SOD) and catalase (CAT), decreased the contents of reactive oxygen species (ROS) and malondialdehyde (MDA). Isoliquiritin thus provides protective action against cortisone-induced cell damage by reducing oxidative stress. Pretreatment with isolquiritin prevented cortisone-induced mitochondrial damage. Isoliquritin attenuated intra-cellular calcium [Ca] overload.  Thus isoliquitrin exhibits cytoprotective and neuroprotective effects. [19]

Liquid extract of yashtimadhu-licorice (Glycyrrhiza glabra) containing isoliquiritin inhibited granuloma angiogenesis. Isoliquiritin thus exhibits antiangiogenic effect. Needless to say the effect is dose dependent. [20]

Isoliquiritin extracted from root of yashtimadhu-licorice (Glycyrrhiza glabra) and its derivatives displayed hypoglycemic   effects in Swiss albino male mice. [21]

Isoliquiritin apioside from yashtimadhu-liquorice (Glycyrrhiza glabra) shows a marked potential to combat oxidative stress- induced genotoxicity. [22]

Licochalcone A
Molecular formula: C21H22O4
Structural formula:





Licochalcone A is a chalconoid, a type of natural phenols. It was first identified in the root and rhizome of yashtimadhu-licorice (Glycyrrhiza glabra). It shows pleotropic pharmacological actions. [23]

Licochalcone A displays a strong anti-inflammatory activity. Licochalcone A could be an anti-inflammatory drug for future. [24]

Acne is inflammation of sebaceous glands. Moisturizers and anti-inflammatory agents are useful in controlling this condition. A study shows that the combination of licochalcone A, L-carnitine and 1, 2-decanediol is useful in this regard. In this formulation, licochalcone A has anti-inflammatory effect, L-carnitine decreases sebum production and 1, 2-decanediol   has anti-bacterial effect. [25] 

Licochalcone A a major ingredient of yashtimadhu-licorice (Glycyrrhiza glabra) effectively inhibits sUV-induced COX-2 expression and prostaglandin E2 PGE2 generation through the inhibition of activator protein 1 (AP-1) transcriptional           activity. This protects the skin from UV radiation. Researchers feel Licochalcone A may have potential for development as a skin cancer chemopreventive agent. [26]

Licochalcone A also displays antibacterial, antiviral (especially against influenza nuraminidase) and antimalarial activities. Its anti-inflammatory activity is useful as a skin lightening agent particularly for acne rosacea and atopic dermatitis. [27]

Yashtimadhu-licorice (Glycyrrhiza glabra) contains many varieties of licochalcone such as licochalcone A B C etc. They display a strong antioxidant activity [28]

By virtue of its antioxidant property licochalcone A suppresses the proliferation of certain cancer cells. [29]
Licochalcone A showed a dose dependent muscle relaxant effect in carbachol (at effective concentration 50%)-induced bladder contraction. Pretreatment with licochalcone A enhanced the relaxant effect of an adenylyl catalase activator, forskolin. [30]

Licochalcone A isolated from Glycyrrhiza species induces apoptosis in cancer cells via Sp 1 and Sp 1  regulatory proteins oral squamous cell carcinoma  [31]  

A study published in Cancer Letter shows that Licochalcone A inhibits the growth of gastric cancer cells by arresting cell cycle progression and inducing apoptosis. The study suggests that licochalcones can be used in future to treat gastric cancers. [32]

Isoangustone A
Molecular formula: C25 H26O6
Structural formula:




 Isoangustone A is a novel flavonoid found many species of Glycyrrhiza and many herbs. Isoangustone A was first isolated from the roots of Glycyrrhiza uralensis (Chinese licorice). Isoangustone A was present in hexane/ethanol extract of Glycyrrhiza  ralensis. Isoangustone A is predominantly known as antineoplastic agent as in a study it induced apoptosis in human prostate cancer cells. [33]

Isoangustone A has anti-inflammatory and anticancer effects. Isoangustone A inhibits cell proliferation by targeting PI3K, MKK4 and MKK7 in human melanoma. [34]

In another study, Isoangustone A present in hexane/ethanol extract of Glycyrrhiza uralensis induced apoptosis in human prostate cancer cells. [35]

Licuraside:
Molecular formula: C26H30O13
Structural formula:




Licuraside is a flavonoid isolated from various Glycyrrhiza species. It inhibits the effects of tyrosinase. It shows antibrowning and depigmenting activity on the skin. It is therefore used in cosmetic creams to lighten the skin color, protect the skin from sun burns. [36], [37]

Roasting of species of Glycyrrhiza with refined honey improves the bioavailability, pharmacological activities and properties of water-soluble phytochemicals such as liquiritin, isoliquiritin, apioside, licuraside and glycyrrhizin. After processing the properties of these phytochemicals were found to have changed for better. According to Ayurveda honey should not be roasted because on roasting honey loses its medicinal properties. Here roasting of honey works as a catalyst. Honey does not take part in pharmacological activity of these phytochemicals. On roasting glycyrrhizin and liquiritin are decomposed. [38] 

Kumatakenin
Molecular formula: C17H14O6
Structural formula:





Kumatakenin is an O-methylated flavonol. Kumatakenin was first isolated from the      flower bud of clove (Syzygium aromaticum). Kumatakenin exhibits significant cytotoxic activity against human ovarian cancer cells, SKOV3 and A2780.

Kumatakenin increases the activity of caspase 3, -8 and -9. Kumatakenin also reduces the expressions of MCP-1 and RANTES which are major determinants of macrophage recruitment at tumor sites in ovarian cancer cells. Moreover kumatakenin inhibits the expression of M2 markers and cancer promoting factors, including IL-10, MMP-2/-9 and VEGF. These studies suggest   that kumatakenin may be a promising drug for the treatment of ovarian cancer. [39]. [40]                                                         

Glyzarin  
Molecular formula: C18H14O4
Structural formula:



Glyzarin is a flavone isolated from yashtimadhu-licorice (Glycyrrhiza glabra) in 1977 by Bhardwaj D. K., Seshadri T. R. and Singh R. Glyzarin is insoluble in water.

Glyzarin exhibits chemical properties and pharmacological actions of flavones. [41], [42]


References:

1. Choi JH et al, Inhibitory activity of diacylglycerol aceyltransferase by glabrol isolated from the roots of licorice, Arch Pharm Res. 2010 Feb; 33(2):237-42 
2. Choi JH et al, Glabrol, an aceytyl-coenzyme A: cholesterol aceyltransferase inhibitor from licorice roots.  J Ethnopharmacol 2007 Apr 4; 110(3):563-6   
3. Suengmok Cho, Hypnotic effects and GABA-ergic mechanism of  licorice (Glycyrhhiza glabra) ethanol extract and its major flavonoid constituent glabrol, https://www.researchgate.net/publication/224867014, April 2012
4. https://pubchem.ncbi.nlm.nih.gov/compound/90479675
5. http://www.hmdb.ca/metabolites/HMDB34515
6. https://books.google.co.in/books?isbn=370916480X 
7. https://pubchem.ncbi.nlm.nih.gov/compound/15559941#section=Top
8. http://www.hmdb.ca/metabolites/HMDB35886
9. http://www.hmdb.ca/metabolites/HMDB39690
10. Xing GX et al, Advances in studies on flavonoids of licorice, Zhongguo Zhong Yao Za Zhi, 2003 Jul; 28(7):593-7 
11. Kitagawa I et al, Chemical studies of Chinese licorice-roots.. I. Elucidation of five new flavonoid     constituents from the roots of Glycyrrhiza glabra L. collected in Xinjiang, Chem Pharm Bull (Tokyo), 1994 May; 42(5): 1056-62  
12. Li W et al, Antimicrobial flavonoids from Glycyrrhiza glabra hairy root cultures, Planta Med. 1998 Dec; 64(8): 746-7 
13. Pu JY et al, Antiviral research of triterpenoids in licorice, Bing Du Xue Bao. 2013 Nov; 29(6): 673-9
15. Peng F et al, A Review: The Pharmacology of Isoliquiritigenin. Phytother Res, 2015 Jul; 29(7):969-77
16. Mahalingam S et al, Effects of isoliquiritigenin on ovarian antral follicle growth and steroidogenesis, Reprod Toxico. 2016 Dec; 66:107-114  
17. https://pubchem.ncbi.nlm.nih.gov/compounds/Isoliquiritin      
18. http://www.hmdb.ca/metabolites/HMDB37318
19. Zhou YZ et al, Protective effect of isoliquitrin against corticosterone-induced neurotoxicity in PC 12 cells, FoodFunct 2017 Mar 22; 8(3): 1235-1244   
20. Kobayashi S et al, Inhibitory effect  of isoliquiritn, a compound in licorice root, on angiogenesis in vivo and tube formation in vitro, Biol Pharm Bull, 1995; Oct; 18(10): 1382-6     
21. Gaur R et al, In vivo anti-diabetic activity of Isoliquiritigenin and liquiritigenin, Phytomedicine. 2014 Mar 15; 21(4):415-22     
22. Evaluation of antigenotoxic activity of isoliquiritin apisode from Glycyrrhiza glabra L. Toxicology in vitro Volume 23, Issue 4, June 2009, Pages 680-
23. https://en.wikipedia.org/wiki/Licochalacone_A
24. Qui Y et al, Anti-inflammatory activity of licochalacone A isolated from Glycyrrhiza inflata, Z Naturforsch C     2008 May-June; 63 (5-6): 361-5      
25. https://clinicaltrials.gov/wiki/ct2/show/NCT022173054
26. Song NR et al, Licochalcone A, a polyphenol present in licorice, suppresses UV-induced COX-2 expression by targeting PI3K, MEK 1 and B0- Raf.     
27. https://en.wikipedia.org/wiki/Licochalcone_A
28. Franceschelli S et al, Licochalcone-C extracted from Glucyrrhiza glabra inhibits lipopolysaccharide- interferon-γ inflammation by improving antioxidant conditions and regulating inducible nitric oxide synthase expression, Molecules , 2011 Jul 6 16 (7): 5720-34.   
29. Chen X et al, Antioxidative andanticancer properties of Licochalcone A from licorice, J Ethnopharmacol. 2017 Feb 23; 198: 331-337    
30. Naqai H et al, Antispasmotic activity of licochalcone A, a species-specific ingredient of Glycyrrhiza inflata roots, J Pharmacol. 2007 Oct; 59(10): 1421-
31. Cho JJet al, Licochalcone A a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma, Int J Oncol. 2014 Aug; 45(2): 667-74  
32. Xiao XY et al, Licochalcone A inhibits growth of gastric cancer cells by arresting cell cycle progression and inducing apoptosis, Cancer Lett. 2011 Mar 1; 302(1): 69-75 
33. https://pubchem.ncbi.nih.gov/compound/Isoangustone_A
34. Song NR et al, Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3K, MKK4 and MKK7 human melanoma, Cancer Prev Res (Phila). 2013 Dec; 6(12): 1293-303  
35. Seon MR et al, Isoangustone A present in hexane/ethanol extract of Glycyrrhiza uralensis induces apoptosis in DU 145 human prostate cancer cells via the activation of DR4 and intrinsic apoptosis pathway, Mol Nutr Food Res. 2010 Sep; 54(9: 1329-99.
36. https://pubchem.ncbi.nlm.nih.gov/compound/6475724#section=Chemical-and-Physical-Properties
37. Fu B et al, Isolation and identification of flavonoids in licorice and a study of their inhibitory effects J Agric Food Chem. 2005 Sep 21; 53(19): 7408-14 
38. Wang M et al, Influence of honey-roasting on the main pharmacological activities and the water-soluble active glycosides of licorice, Afr J Tradit. Complement Altern Med. 2011 Dec 29; 9(2):189-96.  eCollection 2012.
39. https://en.wikipedia.org/wiki/Kumatakenin
40. Woo JH et al, Effect of Kumatakenin Isolated From Cloves on the Apoptosis of Cancer Cells and the Alternative Activation of Tumor-Associated Macrophages, J Agric Foof Chem. 2017 Sep 13; 65(36): 7893-7899. Epub 2017 Sep 5.             
41. Bhardwaj D. K., Seshadri T. R. and Singh R. Glyzarin, a new isoflavone from Glycyrrhiza glabra (1977) 
 http://agris.fao.org/agris-search/search.do?recordID=GB19780226336 
42. http://www.hmdb.ca/metabolites/HMDB295334




Comments

Unknown said…
Isoliquiritin is extracted from the root of Glycyrrhiza uralensis Fisch. It has antidepressant-like effects and antitussive effect. Isoliquiritin

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