key: cord-0037624-rjpm608s
authors: Mamedov, Nazim A.; Egamberdieva, Dilfuza
title: Phytochemical Constituents and Pharmacological Effects of Licorice: A Review
date: 2019-02-12
journal: Plant and Human Health, Volume 3
DOI: 10.1007/978-3-030-04408-4_1
sha: 23b1732eed3391b2a2fa7a1f3a097eb873ad7123
doc_id: 37624
cord_uid: rjpm608s

Licorice (or “liquorice”) is one of most widely used in foods, herbal medicine, and extensively researched medicinal plants of the world. In traditional medicine licorice roots have been used against treating many ailments including lung diseases, arthritis, kidney diseases, eczema, heart diseases, gastric ulcer, low blood pressure, allergies, liver toxicity, and certain microbial infections. Licorice extract contains sugars, starch, bitters, resins, essential oils, tannins, inorganic salts, and low levels of nitrogenous constituents such as proteins, individual amino acids, and nucleic acids. A large number of biological active compounds have been isolated from Glycyrrhiza species, where triterpene saponins and flavonoids are the main constitutes which show broad biological activity. This review examines recent studies on the phytochemical and pharmacological data and describes some side effects and toxicity of licorice and its bioactive components.

Licorice is one of the most widely used and extensively researched medicinal plants of the world (Hoffman 2000; Öztürk et al. 2017) . The word liquorice essentially derives from Old Greek glykyrrhiza, glykys means "sweet," and rhiza is "root" (Schulz et al. 1998 ). One of the main active ingredients is glycyrrhizin, which has a cortisone-like effect. Glycyrrhizin is also 50 times sweeter than sucrose (Brown 1995) . Liquorice has several names such as sweetwood, licorice, liquorice radix, reglisse (French), lakritzeholz (German), Gan Cao (Chinese), Meyan or Beyan (Turkish), and Solodka (Russian) (Mills and Bone 2000) . Licorice roots have been used worldwide as a medicine and flavor in industry for over 4000 years. Medicinal uses of licorice are recorded in texts such as Assyrian Herbal (2000 BC) and Ebers Papyrus (1600 BC) (Lucas 1976; Reid 2001) . Licorice is believed to have originated in Iraq. The most widely distributed species Glycyrrhiza glabra is found in Spain, Italy, Turkey, the Caucasus, Central Asia, and the western part of China whereas Glycyrrhiza uralensis is distributed form Central Asia to Mongolia and China (Hayash et al. 2003) . Various species of licorice are currently grown on commercial scale in Spain, Italy, France, Greece, India, Iran, Iraq, Turkey, Turkmenistan, Uzbekistan, Syria, Afghanistan, Azerbaijan, China, and to a limited extent in England and the United States (Sokolov and Zamotayev 1985; Chevallier 1996) . disease, and arthritis (Saxena 2005) . In Chinese medicine, licorice is used to treat acne and pimples, nervous disorders such as hysteria, irritability, and epilepsy as well as reduce the toxic or drastic action of other herbs, and to harmonize herbal formulas (Zhu 1998) . In earlier studies Kong et al. (1984) showed that root extract of licorice was used to treat diarrhea in mice, whereas Hong et al. (1988) demonstrated strong diuretic activity of licorice in rats. Extract of G. glabra was used to treat emotional irritability in adults (Tsuda et al. 1986 ) and stress (Shirinyan et al. 1988) . Licorice extract was also used to treat eczema (Sheehan and Atherton 1992) , and allergic dermatitis (Sokolov and Zamotayev 1985) .

Pharmacological studies have confirmed that Glycyrrhiza species exhibit a broad range of biological activities. In Table 1 various pharmacological activities of Glycyrrhiza species are presented. Many pharmacological activities, such as hypocholesterolemic and hypoglycemic (Sitohy et al. 1991) , anxiolytic (Ambawade et al. 2001) , antimicrobial (Patil et al. 2009 ), antiviral (Cinati et al. 2003) , preliminary free radical scavenging (Toshio et al. 2003 ), anti-ulcer (Da Nagao et al. 1996 , cytotoxic, antitumor (Hossain et al. 2004) , antiallergic (Ram et al. 2006; Kroes et al. 1997), antidiabetic (Isbrucker and Burdock 2006) , anticarcinogenic (Satomi et al. 2005) , antioxidant (Vaya et al. 1998) , anti-inflammatory (Kakegawa et al. 1992; Fujisawa et al. 2000) , and hepatoprotective activities (Van Rossum et al. 2001; Wu et al. 2006) ; skin eruptions; dermatitis; and eczema (Akhtar et al. 2011) , have been reported for roots of Glycyrrhiza species. The licorice can also be used in the management of impaired learning, dementia, Alzheimer's disease, and other neurodegenerative disorders (Chakravarthi et al. 2012 ).

The antimicrobial activity of plant oils and extracts has been recognized for many years and indicated that it may be attributed to alkaloids, saponins, flavonoids, tannin, glycosides, and phenols (Shinwari et al. 2009 (Meghashri 2009 ), whereas methanolic extracts of G. glabra had more fungicidal effect against Arthrinium sacchari and Chaetomium funicola (Hojo and Sato 2002) . In another study Tharkar et al. (2010) also observed antifungal activity of G. glabra extracts. In the following study Gupta et al. (2008) reported antimicrobial activity of G. glabra against Phytochemical Constituents and Pharmacological Effects of Licorice: A Review Mycobacterium tuberculosis. The ethanol, chloroform, and acetone extracts of licorice showed antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa (Nitalikar et al. 2010) . G. glabra extracts showed high antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus, and Propionibacterium acnes (Nand et al. 2012) . Varsha et al. (2013) Lee et al. (1997) , Lee et al. (2005) , Akhtar et al. (2011) Antidepressant and memory-enhancing activity Gareri et al. (2004) , Sharma (2005, 2006) , Zhao et al. (2006) , Wang et al. (2008) , Chakravarthi et al. (2012) N. A. Mamedov and D. Egamberdieva ATCC 4350 (Statti et al. 2004 ). Shinwari et al. (2009) observed antibacterial activity of G. glabra extracts against Pseudomonas aeruginosa and B. subtilis.

The antibacterial activity of secondary metabolites obtained from Glycyrrhiza species against upper airway respiratory tract bacteria such as Streptococcus pyogenes, Haemophilus influenza, and Moraxella catarrhalis was studied by Tanaka et al. (2001) . The authors observed that licoricidin and coumarin derivatives such as glycyrol, glycyrin, and glycycoumarin exhibited high activity against all tested microorganisms. The compound glabridin, derived from root of G. glabra, was found to be active against both yeast and filamentous fungi (Fatima et al. 2009 ). Glabridin showed various biological activities such as antimicrobial activity against Helicobacter pylori , Staphylococcus aureus (Hatano et al. 2000) , and inflammation (Nerya et al. 2003) . Essential oils derived from G. glabra showed inhibitory effect against Aspergillus flavus (Ali 2013 ).

Licorice and glycyrrhizate compounds have long been used as a potential therapeutic agent for several virus diseases including chronic hepatitis B and C, as well as human acquired immunodeficiency syndrome (AIDS) (Wang et al. 2000; Chen et al. 2004; Orlent et al. 2006; Tandon et al. 2002) . There are other several reports indicating antiviral activity of glycyrrhizin and glycyrrhizic acid, where the compounds inhibited growth and cytopathology of hepatitis A and C (Crance et al. 1990 : Van Rossum et al. 1999 , and immunodeficiency virus (HIV) (Hattori et al. 1989; Plyasunova et al. 1992) . Fiore et al. (2009) observed that glycyrrhizin and its derivatives from Glycyrrhiza glabra reduced hepatocellular damage in chronic hepatitis B and C and they also showed antiviral activity against HIV-1, SARS-related coronavirus, respiratory syncytial virus, arboviruses, vaccinia virus, and vesicular stomatitis virus.

According to Crance et al. (2003) glycyrrhizin has antiviral effect, through an inhibition of viral particle to cell membrane binding, or through cellular signal transduction mechanisms. 18β-Glycyrrhetinic acid was found to be a promising biological alternative for the topical treatment of persistent vulvovaginal candidiasis (Pellatti et al. 2009 ). In another study Cinati et al. (2003) observed in vitro antiviral effects for viruses causing respiratory tract infections like influenza virus and the severe acute respiratory syndrome (SARS) corona virus, and human immunodeficiency virus (HIV). Kuo et al. (2009) studied the potential use of G. uralensis for treatment of human infection by enterovirus type 71 (EV71) which can cause life-threatening meningoencephalitis.

The species of Glycyrrhiza has also been used to treat allergies and other inflammatory diseases (Matsui et al. 2004 ). Shin et al. (2008) studied anti-inflammatory effects of glycyrol (benzofuran coumarin) isolated from G. uralensis and found that glycyrols have potential anti-inflammatory effect. In another study Vibha et al. (2009) reported steroid-like anti-inflammatory activity of constituents derived from licorice root, similar to the action of hydrocortisone. They explained this finding due to inhibition of phospholipase A2 activity, an enzyme critical to numerous inflammatory processes. Matsui et al. (2004) reported that glycyrrhetinic acid (ED 50, 200 mg/kg) showed an inhibitory effect on carrageenan-induced rat paw edema and antiallergic activity. The secondary metabolites of G. glabra, namely glycyrrhizic acid, glabridin, and licochalcone A, showed an anti-inflammatory effect (Tokiwa et al. 2004; Furuhashi et al. 2005; Kang et al. 2005) .

In earlier work Bennett et al. (1980) demonstrated the anti-ulcer activity of deglycyrrhizinated licorice formulations using a rat model of aspirin-induced gastric mucosal damage. It has been found that the formulation promotes healing by increasing mucus production and blood supply to the damaged stomach mucosa, thereby enhancing mucosal healing (Van Marle et al. 1981; Da Nagao et al. 1996) . Masoomeh and Kiarash (2007) reported anti-ulcerogenic effect of carbenoxolone derived from the root of licorice by inhibiting the secretion of gastrin. It has been explained by raising the concentration of prostaglandins in the digestive system by licorice compound that promote mucus secretion from the stomach. Adel et al. (2005) reported on the anti-pepsin effect of secondary metabolites of licorice which prolongs the life span of surface cells in the stomach.

The phytochemical constituents of licorice are reported to demonstrate anticancer effects in in vivo and in vitro studies (Salvi et al. 2003) . For example they inhibit tumor formation and growth in breast (Tamir et al. 2000) , liver (Shiota et al. 1999) , and skin cancer (Liu et al. 1998) . In earlier studies Fukai et al. (1998) reported the inhibitory activity of phenolic compounds such as isoliquiritigenin, semilicoisoflavone B, gancaonin C licoisoflavone B, and licoisoflavanone for the growth of both B. subtilis H17 (wild type) and M45 (recombinationless mutant cells). In another study Sheela et al. (2006) observed that the extract of G. glabra inhibited proliferation of tumor cells and inhibited angiogenesis in in vivo assay. Jo et al. (2005) observed that the ethanol extract of G. uralensis root induced apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells. The ethanolic extract and glycyrrhizin display antiproliferative effects against the MCF-7 in a dose-dependent manner (Dong et al. 2007) . Similar results were observed by Jo et al. (2005) where the ethanol extract of G. uralensis root induced apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells. Yoon et al. (2005) found that licochalcone E from the roots of G. inflate exhibited the most potent cytotoxic effect compared with the known antitumor agents, licochalcone A and isoliquiritigenin. In the studies of Nomura et al. (2002) several compounds derived from G. glabra, namely glyasperin A, gancaonin P, licochalcone B, topazolin, and gancaonin O, showed relatively higher cytotoxic activity against human oral squamous carcinoma cell line HSC-2. In the following studies Yoon et al. (2005) showed that licochalcone E, a new retrochalcone derived from the G. inflata, exhibited the potent cytotoxic effect. Hsu et al. (2004) reported that isoliquiritigenin inhibited proliferation of the human non-small cell lung cancer A549 cell line, inducing apoptosis and locking cell cycle progression in the G1 phase. Similar results were observed by Kanazawa et al. (2003) where isoliquiritigenin inhibited the growth of prostate cancer and suggested the compound as a cancer chemopreventive agent in humans. The results indicate that biologically active compound in the root of licorice might be very useful as antiproliferative and antitumor agents (Rahman and Rashid 2008; Hossain et al. 2004 ).

It has been reported that the extract of G. glabra leaves has been proved to have antioxidant, anti-genotoxic, and anti-inflammatory activities (Siracusa et al. 2011) . Several phytochemical constituents derived from Glycyrrhiza roots are considered as a potential source of antioxidants (Singh 2010; Lateef et al. 2012) . For example in earlier studies Vaya et al. (1997) reported about significant antioxidant activity of isoflavones glabridin and hispaglabridins A and B. Hesham and Shgeru (2002) have reported that flavonoids like luteolin, rutin, and apigenin derived from the root of G. glabra possess antioxidant properties. In the following study phenolic compounds have been reported as the main compound linked to antioxidant activity (Škrovánková et al. 2012) . Muralidharan et al. (2009) have found that the ethanol extract of G. glabra possesses a cerebroprotective effect in hypoxic rats, which may be mediated by its antioxidant effects. Essential oil of G. glabra exhibited DPPH radical scavenging activity (85.2%) at a dose of 400 μg/mL (Ali 2013), whereas methanolic extract exhibited 91.3% scavenging activity at a dose of 62.5 μg (Lateef et al. 2012) . Franceschelli et al. (2011) observed that licochalcone C has antioxidant properties since it reduces the production of superoxide radicals and consequently reduces the activity of inducible nitric oxide synthase (iNOS).

In traditional medicine G. glabra were used to treat various liver diseases (Subramoniam and Pushpangadan 1999) . Later modern medicinal studies showed that secondary metabolites derived from licorice were found to lower serum liver enzyme levels and improve tissue pathology in hepatitis patients (Van Rossum et al. 2001) .

Glycyrrhizic acid induced a significant reduction in serum aminotransferases and improved the liver histology (Curreli et al. 2007 ). In recent studies Al-Razzuqi et al. (2012) demonstrated that the aqueous extract of G. glabra showed a significant effect in ameliorating liver functions in acute liver diseases when it was given in a single dose per day of 2 mg/kg body weight. In another study the protective effects of glycyrrhetinic acid against the carbon tetrachloride-induced hepatotoxicity and retrorsine-induced liver damage were reported (Jeong et al. 2002) .

The bioactive compounds derived from Glycyrrhiza roots have also showed skinwhitening, depigmenting, antiaging, anti-acne, and anti-erythemic properties (Lee et al. 1997) . In recent studies Akhtar et al. (2011) found significant decrease in skin melanin by formulation of G. glabra extracts. Lee et al. (2005) explained that glycyrrhizin derived from the root of G. glabra induced melanin formation that may be mediated via the activation of a tyrosinase gene expression.

Licorice has also been found to have a memory-enhancing activity in passive avoidance paradigm (Dhingra and Sharma 2005) and antidepressant-like activity in mouse immobility tests (Dhingra and Sharma 2006) . Several secondary metabolites derived from G. uralensis, e.g., liquiritin, demonstrated an antidepressant effect on chronic stress-depressed rats (Zhao et al. 2006) . In the following studies Wang et al. (2008) also reported antidepressant-like activity of liquiritin and isoliquiritin in two classic animal behavior despair tests-the Forced Swimming Test (FST) and the Tail Suspension Test (TST) in mice. The authors explained the mechanism of action of those compounds which may be due to increased 5-hydroxytryptamine and norepinephrine in the mouse hippocampus, hypothalamus, and cortex. The other compound carbenoxolone also found in licorice demonstrated sedative and muscle-relaxant activities in mice and in genetically epilepsy-prone rats (GEPRs) (Gareri et al. 2004) . Chakravarthi et al. (2012) studied the impact of root extract of G. glabra on learning and memory in 1-month-old male Wistar albino rats and they found that 150 and 225 mg/kg doses have shown a significant enhancement in learning and memory which is comparable to control. They explained that such improvement is due to antioxidant and anti-inflammatory action of plant extract where susceptible brain cells get exposed to less oxidative stress resulting in reduced brain damage and improved neuronal function.

There are also many studies reporting on the various pharmacological activities of licorice extract and biologically active compounds. For example the secondary metabolites liquiritigenin and isoliquiritigenin derived from the root of G. glabra showed dose-related antiallergic activities (Kakegawa et al. 1992) . Mishra et al. (2011) evaluated the anti-arthritic activity of G. glabra by significant reduction of paw edema volume and its capacity to stabilize lysosomal enzyme activity such as ACP significantly. The results justified the benefit of G. glabra in the treatment of inflammation-associated diseases like arthritis. Asgary et al. (2007) investigated the effect of G. glabra extract on blood lipids and atherosclerosis in rabbits fed with high-cholesterol diet. The authors found that G. glabra extract significantly decreased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels and increased high-density lipoprotein cholesterol (HDL-C) and lessened atherosclerotic lesion in aorta. Similar results were observed by Fuhrman et al. (2002) where G. glabra extract decreased TC, TG, and LDL cholesterol and increased HDL cholesterol in hypercholesterolemic patients. Won et al. (2007) reported the use of licorice as food ingredients for obesity. They observed that licochalcone A derived from G. uralensis reduced the lipase activity as a new inhibitor of pancreatic lipase.

Biologically active compounds are primarily secondary metabolites and their derivatives such as alkaloids (Sarker and Nahar 2007; Varsha et al. 2013) , glycosides (Firn 2010) , flavonoids (Kar 2007; Varsha et al. 2013) , phenolics (Cai et al. 2004; Puupponen-Pimiä et al. 2001) , saponins (Sarker and Nahar 2007; Vashist and Sharma 2013) , tannins (Kar 2007; Varsha et al. 2013) , terpenes (Martinez et al. 2008) , anthraquinones (Maurya et al. 2008; Vashist and Sharma 2013) , essential oils (Martinez et al. 2008; Vashist and Sharma 2013) , and steroids (Madziga et al. 2010; Varsha et al. 2013) .

Licorice extract contains sugars, starch, bitters, resins, essential oils, tannins, inorganic salts, and low levels of nitrogenous constituents such as proteins, individual amino acids, and nucleic acids (Hoffmann 1990; Isbrucker and Burdock 2006) . According to Zhang and Ye (2009) more than 400 compounds have been isolated from Glycyrrhiza species, where triterpene saponins and flavonoids are the main constituents which showed broad biological activity.

It has been reported that more than 300 flavonoids have been found in various species of Glycyrrhiza (Herz et al. 1998; Li et al. 2000) . Among them the commonly used flavonoid types are flavanones, chalcones, isoflavanes, isoflavenes, flavones, and isoflavones (Lou and Qin 1995; Xing et al. 2003) . G. glabra has yellow color due to the flavonoids, e.g., liquiritin and isoliquiritin (Yamamura et al. 1992) . A number of licorice flavonoids were identified: liquiritin, liquiritigenin, rhamnolliuiritin, liquiritin apioside, gralbranin, glabrol, licoflavanone, isoliquiritigenin, neoisoliquiritin, licuraside, licochalcone A and B, licoricidin, 7-methillicoricidin, hispaglabridin A and B, liocflavone A and B, liocflavanol, glyzaglabrin, licoisoflavanone, glabroisoflavanone, glabrone, licoricone, and gancaonin (Zhang and Ye 2009) . Hatano et al. (1998) isolated flavonoid glycosides with feruloyl or coumaroyl groups and with an indole conjugate. Ma et al. (2005) isolated and identified bioactive flavonoid compounds, liquiritigenin and isoliquiritigenin, from the crude extract of G. uralensis Risch. Franceschelli et al. (2011) identified licochalcone C, the structural isomer of licochalcone A. Other flavonoids such as licoagrodin, licoagrochalcones, glyinflanin B, and glycyrdione A were also reported by several studies (Asl and Hosseinzadeh 2008; Christensen and Kharazmi 2001; Li et al. 2000) . Gupta et al. (2008) identified glabridin and hispaglabridin B from ethanolic extract of the roots of G. glabra. Manfredi et al. (2001) isolated and identified bioactive compounds glepidotin B and glepidotin A from the extract of G. lepidota. Williamson (2003) isolated and identified isoflavonoid derivatives, namely glabridin, galbrene, glabrone, shinpterocarpin, licoisoflavones A and B, formononetin, glyzarin, and kumatakenin. In other studies hispaglabridin A, hispaglabridin B, 4′-O-methylglabridin, and 3′-hydroxy-4′-O-methylglabridin were identified from Glycyrrhiza species. Won et al. (2007) isolated and identified licochalcone A from the ethyl acetate extract of the roots of G. uralensis. Kinoshita et al. (2005) identified several compounds from the root of G. glabra, namely glabridin, galbrene, glabrone, shinpterocarpin, licoisoflavones A and B, formononetin, glyzarin, kumatakenin, hispaglabridin A, hispaglabridin B, glabroisoflavanone A and B, and glabroisoflavanone B.

The root of Glycyrrhiza contains triterpenoid saponins (glycyrrhizin, glycyrrhizic acid), which are the major characteristic constituents of liquorice, and they are responsible for the sweet taste (Blumenthal et al. 2000) . Glycyrrhizic acid is the major triterpenoid saponin in licorice root and the main sweetener of the herb which is 50 times sweeter than sugar . Glycyrrhizin and the aglycone of glycyrrhizin are believed to speed the healing of gastric ulcers (Amirova 1993; Blumenthal et al. 2000) . Glycyrrhetic acid has shown anti-inflammatory and antiarthritic activities in animal studies (Amirova 1993) . Isbrucker and Burdock (2006) described other triterpenes, namely liquiritic acid, glycyrretol, glabrolide, isoglaborlide, and licorice acid. Fenwick et al. (1990) described two aglycone forms of glycyrrhizic acid 18β-glycyrrhetinic acid and 18α-glycyrrhetinic acid. Vashist and Sharma (2013) reported about the presence of ammonium glycyrrhizinate (3.4%) and calcium glycyrrhizinate (4%) in the ethanolic extract of G. glabra. Zhang and Ye (2009) described several saponins derived from Glycyrrhiza species, namely licorice-saponin A3, 22β-actoxylglycyrrhizin, uralsaponin B, apioglycyrrhizin, araboglycyrrhizin, and icorice-saponin E2.

There are many reports on the phenolic constituents of Glycyrrhiza species . The main phenols include liquiritin, isoliquiritin, liquiritin apioside, and isoprenoid-substituted flavonoids, chromenes, coumarins, and dihydrostilbenes. Nomura et al. (2002) studied phenolic compounds from various Glycyrrhiza species, and found isoprenoid-substituted flavonoid (pyranoisoflavan, glabridin) (G. glabra), isoflavans (G. uralensis), licochalcone A (G. inflate, G. eurycarpa), licoricidin (6), and licorisoflavan A (G. aspera). For example isobavachin is observed in G. pallidiflora, sigmoidin B in G. uralensis, and liquiritigenin in Glycyrrhiza species . Zhang and Ye (2009) described several phenolic compounds derived from Glycyrrhiza species including glycycoumarin, glabrocoumarin, glycyrin, inflacoumarin A, licopyranocoumarin, isoglycerol, neoglycerol, licobenzofuran, licocoumarone, glabrocoumarone, gancaonin, and kanzonol. In another study Ammar et al. (2012) isolated phenolic compounds, namely liquiriteginin, liquiritin apioside, neoliquiritin apioside, isoliquiritin, isoliquritin apioside, licuraside2-(5-P-coumaryl apiosyl), and isoliquiritin from the total polar extract of G. glabra utilizing different chromatographic techniques.

Isolation and identification of isoliquiritigenin from licorice grown in China have been reported by Chin et al. (2007) and liquiritin by Huang et al. (2010) . Zhu et al. (2008) studied biologically active compounds of G. uralensis collected in Mongolia and found three flavanone constituents (liquiritin apioside, liquiritin, and liquiritigenin) and three chalcones (isoliquiritin apioside, isoliquiritin, and isoliquiritigenin). Similar observation was reported by Williamson (2003) who identified liquiritin, liquiritigenin, rhamnoliquiritin, neoliquiritin, chalcones isoliquiritin and isoliquiritigenin, neoisoliquiritin, licuraside, glabrolide, and licoflavonol.

Several coumarins were identified from G. glabra including liqcoumarin, glabrocoumarone A and B, herniarin, umbelliferone, and glycyrin (Williamson 2003). Kinoshita et al. (2005) studied coumarins from the Glycyrrhiza plants and identified liqcoumarin, glabrocoumarone A and B, herniarin, umbelliferone, glycocoumarin, licofuranocoumarin, licopyranocoumarin, and glabrocoumarin. In recent studies Qiao et al. (2014) identified glycerol, glycycoumarin, and dehydroglyasperin from the root extract of G. uralensis. De Simone et al. (2001) described two coumarins of G. glabra, glycocoumarin and licopyranocoumarin, which were able to inhibit giant cell formation in HIV-infected cell cultures.

Other secondary metabolites such as fatty acids, phenol, guaiacol, asparagines, glucose, sucrose, starch, polysaccharides, and sterols (β-sitosterol, dihydrostigmasterol) have also been found and reported by Näf and Jaquier (2006) . Ali (2013) studied essential oil composition of G. glabra and found compounds such as α-pinene, β-pinene, octanol, γ-terpinene, stragole, isofenchon, β-caryophyllene, citronellyl acetate, caryophyllene oxide, and geranyl hexanolate. Among those compounds geranyl hexanolate represents higher percentage (34%) whereas β-pinene was the lowest (1.7%). Khalaf et al. (2010) studied phytoestrogens from roots of G. glabra from Syria and identified daidzein, daidzin, genistin, ononin, glycitein, genistein, and coumestrol. Sultana et al. (2010) described dihydrostilbenes from the root extract of G. glabra grown in Sicily.

The potentially toxic compounds in licorice are unconfirmed, although deglycyrrhinized licorice (DGL) is reported to be free of adverse effects. The toxic effects of licorice are well documented. Large amounts of licorice may result in severe hypertension, hypokalemia, and other signs of mineralocorticoid excess (Asl and Hosseinzadeh 2008) .

Large doses (more then ten times the standard dose) taken over a long period of time can lead to a number of dangerous conditions (McGuffin et al. 1997) . The use of licorice is contradicted in persons with high blood pressure due to hypertension caused by overuse of licorice (Olukoga and Donaldson 2000) . This is thought to be due to the effect of licorice on the aldosterone system . Al-Qarawi et al. (2002) report the treatment with licorice extract resulted in dosedependent increases in plasma renin and sodium with concomitant decreases in plasma cortisol, adrenocorticotropic hormone (ACTH), aldosterone, and potassium levels.

Prolonged use of licorice could result in hypertension, hypokalemia, and edema (DeSmet et al. 1997; Asl and Hosseinzadeh 2008) . It is also speculated that since insulin-dependent diabetics appear to be predisposed to hypokalemia and sodium retention, licorice use is contradicted by diabetes (McGuffin et al. 1997; Isbrucker and Burdock 2006) .

Licorice should not be used with stimulant laxatives or hypotensive diuretics (such as thiazides) because of the potassium loss associated with the laxatives and diuretics (DeSmet et al. 1997; Asl and Hosseinzadeh 2008) . In earlier studies glycyrrhizin has been shown to interfere with 5β-reductase breakdown of corticosteroids, thus prolonging the biological half-life of these steroids. The licorice constituent glycyrrhizin or the aglycone, glycyrrhetinic acid, may increase the effect of corticoid treatment (Brinker 1997) (Table 2) .

Licorice (Glycyrrhiza) a leguminous plant and the roots have been used worldwide as a medicine and flavor in industry. It is estimated that more than 400 compounds have been isolated from Glycyrrhiza species, where triterpene saponins and flavonoids are the main constituents which showed broad biological activity. The Phytochemical Constituents and Pharmacological Effects of Licorice: A Review triterpenoid saponins (glycyrrhizin, glycyrrhizic acid), which are the major characteristic constituents of liquorice, are responsible for the sweet taste. The main phenols include liquiritin, isoliquiritin, and coumarins including liqcoumarin and glabrocoumarone A and B. Pharmacological studies have confirmed that plant extracts and individual biologically active compounds exhibit a broad range of biological activities such as antimicrobial, antiviral, anti-ulcer, antitumor, antioxidant, antiallergic, neuroprotective, anti-inflammatory, hepatoprotective, and dermatological activities. The Glycyrrhiza plant can also be used in the management of impaired learning, dementia, and Alzheimer's disease. The potentially toxic compounds in licorice are unconfirmed, whereas the toxic effects of licorice plant are well documented. Large doses taken over a long period of time can lead to a number of severe disorders. From these data and reports it can be concluded that licorice can be used as a therapeutic drug in low doses for major body ailments and presents no concern for safe use.

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Anti oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra)

Antimalarial natural products. In: Tringali C (ed) Bioactive compounds from natural sources: isolation, characterization and biological properties

Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus

Inhibition of hepatitis A virus replication in vitro by antiviral compounds

Interferon, ribavirin, 6-azarridine and glycyrrhizin: antiviral compounds active against pathogenic flaviviruses

Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice

Effectiveness of glycyrrhizin for oral lichen planus in patients with chronic HCV infection

Medicinal uses of licorice through the millennia: the good and plenty of it

Adverse effects of herbal drugs

Evaluation of antidepressant-like activity of glycyrrhizin in mice

Antidepressant-like activity of Glycyrrhiza glabra L. in mouse models of immobility tests

Activation of rapid signaling pathways and the subsequent transcriptional regulation of breast cancer MCF-7 by the treatment with an extract of Glycyrrhiza glabra root

Antifungal activity of Glycyrrhiza glabra extracts and its constituent glabridin

Liquorice, Glycyrrhiza glabra L. composition, uses and analysis

A history of the therapeutic use of liquorice in Europe

Antiviral effects of Glycyrrhiza species

Nature's chemicals: the natural products that shaped our world

Licocalchone-C extracted from Glycyrrhiza glabra inhibits lipopolysaccharide-interferon-gamma inflammation by improving antioxidant conditions and regulating inducible nitric oxide synthase expression

Antiatherosclerotic effect of licorice extract supplementation on hypercholestrolomic patients

Glycyrrhizin inhibits the lytic pathway of complement-possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis

An isoprenylated flavanone from Glycyrrhiza glabra and rec-assay of licorice phenols

Anti-Helicobacter pylori flavonoids from licorice extract

Inhibition by licochalcone A, a novel flavonoid isolated from liquorice root, of IL-1β-induced PGE2 production in human skin fibroblasts

Anticonvulsant effects of carbenoxolone in genetically epilepsy prone rats (GEPRs)

Antimicrobial potential of Glycyrrhiza glabra roots

Acylated flavonoid glycosides and accompanying phenolics from licorice

Phenolic constituents of licorice. VIII. Structures of glicophenone and glicoisoflavanone, and effects of licorice phenolics on methicillin resistant Staphylococcus aureus

Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS

Field survey of Glycyrrhiza plants in Central Asia: chemical characterization of G. glabra collected in Uzbekistan

Chemistry of bioflavonoids

Easy breathing: natural treatments for asthma, colds, flu, coughs, allergies, sinusitis

Antifungal activity of licorice (Glycyrrhiza glabra) and potential applications in beverage

Studies on the efficacy of combined preparation of crude drugs. Effects of sipmidojuksan on the central nervous and cardiovascular systems

Antimicrobial and cytotoxic activities of 2-aminobenzoic acid and 2-aminophenol and their coordination complexes with magnesium (Mg-II)

Isoliquiritigenin inhibits the proliferation and induces the apoptosis of human non-small cell lung cancer A549 cells

Investigation on medicinal plant resources of Glycyrrhiza uralensis in China and chemical assessment of its underground part

Risk and safety assessment on the consumption of licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin

Hepatoprotective effects of 18β-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression

Chemopreventive properties of the ethanol extract of Chinese licorice (Glycyrrhiza uralensis) root: induction of apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells

Inhibitory effects of some natural products on the activation of hyaluronidase and their anti-allergic actions

Isoliquiritigenin inhibits the growth of prostate cancer

Glabridin, an isoflavan from licorice root, inhibits inducible nitric-oxide synthase expression and improves survival of mice in experimental model of septic shock

Pharmacognosy and pharmacobiotechnology

Hplc-Ms study of phytoestrogens from Glycyrrhiza glabra

The isolation and structure elucidation of minor isoflavonoids from licorice of Glycyrrhiza glabra origin

Studies on the efficacy of combined preparation of crude drugs: effects of "Bojungikgi-tang" on the digestive system, blood pressure and diuretic actions

Inhibition of human complement by beta-glycyrrhetinic acid

Water extract of Glycyrrhiza uralensis inhibited enterovirus 71 in a human foreskin fibroblast cell line

Evaluation of antioxidant and urease inhibition activities of roots of Glycyrrhiza glabra

Biological screening of 100 plant extracts for cosmetic use (I): inhibitory activities of tyrosinase and DOPA auto-oxidation

Glycyrrhizin induces melanogenesis by elevating a camp level in b16 melanoma cells

Flavonoid constituents from Glycyrrhiza glabra hairy root cultures

The herbal medicine Sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas mediated apoptosis and arresting cell cycle through down regulation of cyclin dependent kinases

Species systematization and quality evaluation of commonly used Chinese traditional drugs

Nature's medicines

One step isolation and purification of liquiritigenin and isoliquiritigenin from Glycyrrhiza uralensis Risch. using high-speed counter-current chromatography

Phytochemical and elemental analysis of Acalypha wilkesiana leaf

Isolation of an anti-HIV diprenylated bibenzyl from Glycyrrhiza lepidota

Anti-infectious activity in the Anthemideae tribe

In vitro susceptibility of Helicobacter pylori to licorice extract

Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line

Antiosteoporotic agents from natural sources

Botanical safety handbook

In vitro antifungal and antibacterial activities of root extract of Glycyrrhiza glabra

Principles and practice of phytotherapy: modern herbal medicine

Anti-arthritic activity of Glycyrrhiza glabra, Boswellia serrata and their synergistic activity in combined formulation studied in Freund's adjuvant induced arthritic rats

Cerebroprotective effect of Glycyrrhiza glabra Linn. root extract on hypoxic rats

New lactones in liquorice (Glycyrrhiza glabra L.)

Phytochemical and antimicrobial screening of medicinal plants for the treatment of acne

Glabrene and isoliquiritigenin as tyrosinase inhibitors from liquorice roots

Studies of antibacterial activities of Glycyrrhiza glabra root extract

Phenolic constituents of licorice (Glycyrrhiza species)

Chemistry of phenolic compounds of licorice (Glycyrrhiza species) and their estrogenic and cytotoxic activities

Liquorice and its health implications

Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial

Liquorice-from botany to phytochemistry, Springer briefs in plant sciences

Antimicrobial activity of Glycyrrhiza glabra Linn. Roots

In vitro effects of glycyrrhetinic acid on the growth of clinical isolates of Candida albicans

Antiviral activity of licorice

Antimicrobial properties of phenolic compounds from berries

Simultaneous determination of five minor coumarins and flavonoids in Glycyrrhiza uralensis by solid-phase extraction and highperformance liquid chromatography/electrospray ionization tandem mass spectrometry

Antimicrobial activity and cytotoxicity of Eclipta prostrata

Glycyrrhizin alleviates experimental allergic asthma in mice

Glycyrrhetinic acid-induced permeability transition in rat liver mitochondria

Chemistry for pharmacy students: general, organic and natural product chemistry

Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2

Glycyrrhiza glabra: medicine over the millennium

Rational phytotherapy. A physicians' guide to herbal medicine

Glycyrrhiza glabra-a plant for the future

Phytochemical screening and determination of antibacterial and anti-oxidant potential of Glycyrrhiza glabra root extracts

A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema

Angiogenic and proliferative effects of the cytokine VEGF in Ehrlich ascites tumor cells is inhibited by Glycyrrhiza glabra

Anti-inflammatory effects of glycyrol isolated from Glycyrrhiza uralensis in LPSstimulated RAW264.7 macrophages

Assessment of antibacterial activity of three plants used in Pakistan to cure respiratory diseases

Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice

New antistressor compounds from licorice

Comparative phytochemical and antioxidant study of aqueous extracts of Glycyrrhiza glabra (mulethi) and Piper longum (long pepper)

Phytocomplexes from liquorice (Glycyrrhiza glabra L.) leaves-chemical characterization and evaluation of their antioxidant, anti-genotoxic and anti-inflammatory activity

Metabolic effect of licorice roots (Glycyrrhiza glabra) on lipid distribution pattern, liver and renal functions of albino rats

Chapter 3-Antioxidant activity and protecting health effects of common medicinal plants

Directory of medicinal plants

Variability in the content of active constituents and biological activity of Glycyrrhiza glabra

Development of phytomedicines for liver diseases

Antimicrobial, cytotoxic and antioxidant activity of methanolic extract of Glycyrrhiza glabra

Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells

Antibacterial compounds of licorice against upper airway respiratory tract pathogens

Clinical spectrum of acute sporadic hepatitis E and possible benefit of glycyrrhizin therapy

Antifungal activity of Glycyrrhiza glabra Linn. and Emblica officinalis Gaertn. by direct bioautography method

Oriental medicinal herb, Periploca sepium, extract inhibits growth and IL-6 production of human synovial fibroblast-like cells

Preliminary evaluation of anti nephritis and radical scavenging activities of glabridin from Glycyrrhiza glabra Linn

Kanbalu-Taiso-To" on transmembrane ionic currents and its local anesthetic action

Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium

Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection

Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C

Phytochemical screening and determination of antibacterial and anti-oxidant potential of Glycyrrhiza glabra root extracts

Pharmacognostical aspects of Glycyrrhiza glabra

Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation

Structural aspects of the inhibitory effect of glabridin on LDL oxidation

A Study on pharmacokinetics and therapeutic efficacy of Glycyrrhiza glabra: a miracle medicinal herb

Licorice in foods and herbal drugs: chemistry, pharmacology, toxicology and uses

Antidepressantlike effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice

Potter's cyclopedia of herbal medicine

Licochalcone A: a lipase inhibitor from the roots of Glycyrrhiza uralensis

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Advances in studies on flavonoids of licorice

Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method

Cytotoxic allylretrochalcone from the roots of Glycyrrhiza inflate

Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice)

Anti-depressive effect of liquiritin on chronic stress depression in rats

Chinese materia medica: chemistry, pharmacology and applications

Survey of Glycyrrhizae Radix resources in Mongolia: chemical assessment of the underground part of Glycyrrhiza uralensis and comparison with Chinese Glycyrrhizae Radix