key: cord-0010169-67cy11ah
authors: Asl, Marjan Nassiri; Hosseinzadeh, Hossein
title: Review of Pharmacological Effects of Glycyrrhiza sp. and its Bioactive Compounds
date: 2008-04-29
journal: Phytother Res
DOI: 10.1002/ptr.2362
sha: 4126bf38ea18d91466f09d0e1478dbddcf471247
doc_id: 10169
cord_uid: 67cy11ah

The roots and rhizomes of licorice (Glycyrrhiza) species have long been used worldwide as a herbal medicine and natural sweetener. Licorice root is a traditional medicine used mainly for the treatment of peptic ulcer, hepatitis C, and pulmonary and skin diseases, although clinical and experimental studies suggest that it has several other useful pharmacological properties such as antiinflammatory, antiviral, antimicrobial, antioxidative, anticancer activities, immunomodulatory, hepatoprotective and cardioprotective effects. A large number of components have been isolated from licorice, including triterpene saponins, flavonoids, isoflavonoids and chalcones, with glycyrrhizic acid normally being considered to be the main biologically active component. This review summarizes the phytochemical, pharmacological and pharmacokinetics data, together with the clinical and adverse effects of licorice and its bioactive components. Copyright © 2008 John Wiley & Sons, Ltd.

Licorice species are perennial herbs native to the Mediterranean region, central to southern Russia, and Asia Minor to Iran, now widely cultivated throughout Europe, the Middle East and Asia (Blumenthal et al., 2000) . They have been used medically since at least 500 BC and licorice has been described as 'the grandfather of herbs' (Ody, 2000) . The genus Glycyrrhiza (Leguminosae) consists of about 30 species including G. glabra, G. uralensis, G. inflata, G. aspera, G. korshinskyi and G. eurycarpa, G. glabra also includes three varieties: Persian and Turkish licorices are assigned to G. glabra var. violacea, Russian licorice is G. glabra var gladulifera, and Spanish and Italian licorices are G. glabra var. typica (Nomura et al., 2002) . It is also known as liquorice, kanzoh, gancao, sweet root and yasti-madhu (Blumenthal et al., 2000; Nomura et al., 2002) .

Licorice root contains triterpenoid saponins (4-20%), mostly glycyrrhizin, a mixture of potassium and calcium salts of glycyrrhizic acid (also known as glycyrrhizic or glycyrrhizinic acid, and a glycoside of glycyrrhetinic acid) which is 50 times as sweet as sugar (Blumenthal et al., 

Antiinflammatory activities β-glycyhrritinic acid has shown antiinflammatory properties in different animal models (Capasso et al., 1983; Amagaya et al., 1984; Inoue et al., 1989) . β-Glycyhrritinic acid is the major metabolite of glycyrrhizin (Gumpricht et al., 2005) .

Two mechanisms have been suggested for the antiinflammatory effects of β-glycyhrritinic acid: First, it inhibits glucocorticoid metabolism and potentiates their effects. This potentiation was reported in skin and lung after coadministration of them with β-glycyhrritinic acid (Teelucksingh et al., 1990; Schleimer, 1991) . Since, β-glycyhrritinic acid is a potent inhibitor of 11βhydroxysteroid hydroxygenase (Walker and Edwards, 1991) , it causes an accumulation of glucocorticoids with antiinflammatory properties. Oral administration of β-glycyhrritinic acid or glycyrrhizin confirmed this result (MacKenzie et al., 1990) . Second, it inhibits classical complement pathway activation and its activity is dependent on its conformation (Kroes et al., 1997) . Thus, it is suggested that co-medication of it with hydrocortisone in the treatment of inflammatory lung disease will be useful (Schleimer, 1991) .

Glycyrrhizin inhibited reactive oxygen species (ROS) generation by neutrophils which are the potent mediator of tissue inflammation in the in vitro study. It was thought that one of its antiinflammatory effect was due to this inhibitory effect (Akamatsu et al., 1991 ; Wang and Nixon, 2001) . Also, the generation of reactive oxygen species was also suppressed by glabridin treatment in RAW 264.7 cells (Jong et al., 2005) .

G. glabra and glyderinine, a derivative of glycyrrhizic acid, showed an antiinflammatory effect (Azimov et al., 1988; Tokiwa et al., 2004) . It also reduced myocardial inflammatory edema in experimental myocardial damage (Zakirov et al., 1999) . In addition, glabridin and lichochalocone A have shown an antiinflammatory effect in in vivo studies Jong et al., 2005) .

Glycyrrhetinic acid did not inhibit either cyclooxygenase 1 or 2 catalysed prostaglandin biosynthesis with an IC 50 value of 425 μM in an in vitro study (Perera et al., 2001) . However, in another study G. radix was believed to be involved in COX-2 inhibition (Kase et al., 1998) . Furthermore, in this paper G. radix increased corticosterone levels in rats. Also, glycyrrhizin and glycyrrhetinic acid are known to inhibit phospholipase A 2 (Kase et al., 1998) . Recently, some derivatives of glycyrrhetinic acid have shown their inhibitory activity against interleukin-1b (IL-1b)-induced prostaglandin E2 (PGE2) production in normal human dermal fibroblasts (NHDF) (Tsukahara et al., 2005) .

The methanol extract of aerial parts of G. glabra showed antibacterial activity against several kinds of bacteria (Sabahi et al., 1987) . Several flavonoids with C5 aliphatic residues were isolated as the effective constituents of licorice against methicillin-resistant Staphylococcus aureus (MRSA) and restored the effects of oxacillin and βlactam antibiotic against MRSA (Hatano et al., 2000b (Hatano et al., , 2005 . Glabridin, glabrene and licochalcone A exhibited antimicrobial activity against Helicobacter pylori in vitro (Fukai et al., 2002a (Fukai et al., , 2002b . The ether-water extracts of G. glabra were found to have effective antibacterial activity against all the five bacteria, E. coli, B. subtilis, E. aerogenes, K. pneumoniae and S. aureus (Onkarappa et al., 2005) . Glycyrrhizol A and 6, 8-diisoprenyl-5, 7 , 4′-trihydroxyisoflavone from the root of G. uralensis exhibited potent antibacterial activity against Streptococcus mutans with minimum inhibitory concentrations of 1 and 2 μg/mL, respectively (He et al., 2006) .

Glycyrrhizic acid inhibits the replication of several viruses in vitro (Table 2) and some mechanisms have been found for the antiviral effects of glycyrrhizin (Van Rossum et al., 1998; Cohen, 2005) . In another study glycyrrhizic acid induced apoptosis of primary effusion lymphoma (PEL) cells that were transformed by Kaposi sarcoma-associated herpesvirus (KSHV) and terminated latent infection in B lymphocytes (Curreli et al., 2005) .

Two coumarins of G. glabra, glycocoumarin and licopyranocoumarin, were able to inhibit giant cell formation in HIV-infected cell cultures without any cytotoxicity (Hatano et al., 1988; De Simone et al., 2001) (Fig. 2) . Takahara et al., 1994; Sato et al.,1996 Hepatitis C virus (HCV) Van Rossum et al., 1998 Human cytomegalovirus (CMV) Numazaki et al., 1994 Human immunodeficiency virus (HIV) Ito et al., 1988 Influenza virus Utsunomiya et al., 1997 SARS coronavirus Cinatl et al., 2003 Varicella zoster virus (VZV) Baba and Shigeta, 1987 Figure 2. Anti-HIV coumarins isolated from G. glabra.

E-deficient (E 0 ) mice caused a significant reduction not only in their LDL oxidation but also in the development of atherosclerotic lesions (Fuhrman et al., 1997; Rosenblat et al., 1999) . It seems that glabridin may possess this property by two mechanisms: first it binds to the LDL and substantially protects its oxidation (Fuhrman et al., 1997; Belinky et al., 1998a) . The hydroxyl groups on the B ring of glabridin were found to be most important for its antioxidative properties (Belinky et al., 1998b) . Second it accumulates in cells such as macrophages, causing a reduction of cellular oxidative stress by reducing NADPH oxidase activation and increasing cellular glutathione (GSH) (Rosenblat et al., 1999 (Rosenblat et al., , 2002 . In addition, other constituents of G. glabra such as isoflavones hispaglabridin A, hispaglabridin B and 4′-O-methylglabridin, the two chalcones, isoprenylchalcone derivative and isoliquiritigenin were antioxidants against LDL oxidation .

In an in vitro study, glycyrrhizin was hepatoprotective, probably by preventing changes in cell membrane permeability (Nakamura et al., 1985) . Nevertheless, it was suggested that glycyrrheitinic acid is a better hepatoprotective drug than glycyrrhizin in in vitro study (Nose et al., 1994) . This observation is in keeping with the protective effects of glycyrrhetinic acid against the carbon tetrachloride-induced hepatotoxicity and retrorsine-induced liver damage, respectively, in mice and rats (Lin et al., 1999; . Furthermore, in a hepatocyte model of cholestatic liver injury, glycyrrhizin exhibited pro-apoptotic properties, whereas glycyrrheitinic acid is a potent inhibitor of bile acidinduced apoptosis and necrosis (Gumpricht et al., 2005) . Some hepatoprotective effects of glycyrrhizin have been summarized in Table 3 .

The aqueous extract of G. glabra inhibits the in vivo and in vitro proliferation of Ehrlich ascites tumor cells and inhibits angiogenesis in in vivo assay, peritoneal and chorioallantoic membrane assays (Sheela et al., 2006) . Also, the ethanol extract of G. uralensis root induced apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells (Jo et al., 2005) . On the other hand, there are many studies about the anticancer effects of several derivatives of its components both

Chinese licorice roots which can be obtained from the three species of Glycyrrhiza genus, G. glabra, G. uralensis or G. inflata, were found to potentially inhibit the growth of Plasmodium. falciparum and Leishmania donovani in in vitro studies (Christensen et al., 1994; Christensen and Kharazmi, 2001) . Chalcones such as licochalcone A from Chinese licorice roots are known to possess antiplasmodial activity with IC 50 values between 4.5 and 0.6 mg/mL (Chen et al., 1994b; Jenett-Siems et al., 1999) . Also, chalcones have a potent antileishmanial activity and might be developed into a new class of antileishmanial drugs (Chen et al., 1993; Chen, 1994a) . It was found that chalcones, such as lichochalcone A, alter the ultrastructure of the parasite mitochondria and inhibit their function by selectively inhibiting fumarate reductase (FRD) in the respiratory chain of the parasite (Zhai et al., 1995; Chen et al., 2001) .

The constituents of G. inflata, licochalcone A, B, C, D and echinatin, were effective in preventing microsomal lipid peroxidation induced by Fe (III)-ADP/NADPH and licochalcone B, D showed potent antioxidative and superoxide scavenging activities (Haraguchi et al., 1998) . Furthermore, the isoflavone derivatives of G. glabra such as glabridin inhibited lipid peroxidation in rat liver microsomes and protected mitochondrial functions from oxidative stresses (Haraguchi et al., 2000) . Hispaglabridin A, especially, showed a potent antioxidative activity against peroxidation induced by Fe-ascorbate (Haraguchi, 2001) . Moreover, glabridin, an isoflavan of G. glabra, was a potent antioxidant toward LDL oxidation in in vitro and in vivo studies (Fuhrman et al., 1997; Vaya et al., 1997; Belinky et al., 1998a) . The consumption of licorice or glabridin by atherosclerotic apolipoprotein Copyright (Shiki et al., 1992) Deceased LDH and glutamic oxaloacetic transaminase (Nakamura et al., 1985) Increased survival rate of the hepatocyte culture (Nacagiri et al., 2003) Suppressed the elevation lipid peroxides, AST, ALT, LDH and decreased morphological damage (Nagai et al., 1991) Normalized serum levels of transaminase Lin et al., 1999) Normalized serum aminotransferases, alkaline phosphatase and bilirubin (Asgary et al., 2005) Method Incubation with anti-liver cell membrane antibody + complement CCl 4 -induced hepatotoxicity Acetaminophen or D-galactosamine induced liver injury Ischemia-reperfusion damage

Thioacethamide-induced liver damage in in vivo and in vitro studies. For more detail see Table 4 . Glycyrrhetinic acid could also trigger the proapoptotic pathway by inducing mitochondrial permeability transition and this property may be useful for inducing apoptosis of tumor cells (Salvi et al., 2003; Fiore et al., 2004) . Recently, licochalcone E, a new retrochalcone from the roots of G. inflata, exhibited the most potent cytotoxic effect compared with the known antitumor agents, licochalcone A and isoliquiritigenin (Yoon et al., 2005) .

Glabridin inhibited serotonin reuptake (Ofir et al., 2003) . In addition, recently, the aqueous extract of G. glabra L. showed antidepressant activity in both the forced swim test (FST) and tail suspension test (TST) in mice ( Dhingra and Sharma, 2005) . The ethanol extract of G. glabra had an anticonvulsant effect in PTZ and lithiumpilocarpine-induced convulsion models (Ambawade et al., 2002) . Also, the aqueous extract of G. glabra showed memory enhancing effects in the plus-maze and passive avoidance paradigm (Dhingra et al., 2004) . Moreover, chronic administration of the extract of G. glabra in both low and high doses induced correction of the passive avoidance performance in ovariectomized female rats (Fedotova et al., 2005) . Combined treatment with licorice root and vibration resulted in increased succinate dehydrogenase (SDH) activity in different parts of the brain, improved brain energy supply and ameliorated the effect of vibration (Oganisyan et al., 2005) . In addition, isoliquiritigenin showed protective effects in cerebral ischemia-reperfusion injury in rats ( Zhan and Yang, 2006) .

Carbenoxolone has shown anticonvulsant, sedative and muscle relaxant activities in mice and in genetically epilepsy prone rats (GEPRs) (Hosseinzadeh and Nassiri Asl, 2003; Gareri et al., 2004) . Also, it was able to suppress the generation of superoxide anions and hydrogen peroxide in macrophages and it also showed protective effects in the skeletal muscle and hippo-campus against acute ischemic-reperfusion effects in rats (Suzuki et al., 1983; Hosseinzadeh et al., 2005a) . In addition it could decrease the learning performances of rats in a spatial memory task (Hosseinzadeh et al., 2005b) .

Licorice showed an antiplatelet aggregation effect (Tawata et al., 1992; Yu et al., 2005) . In other experiments, glycyrrhizin has been identified as a thrombin inhibitor in in vitro and in vivo studies and it was believed that glycyrrhizin might be used as a model for searching new antithrombotic drugs (Francischetti et al., 1997; Mendes-Silva et al., 2003) . Also, G. glabra accelerated the metabolism of cells in the bone marrow erythroid stem and increased the animal's resistance to stress (Adamyan et al., 2005) .

Isoliquiritigenin, an active component of licorice, is reported to have a vasorelaxant effect ( Yu and Kuo, 1995) . It could also able to decrease tube formation in vascular endothelial cells. Thus, the anti-angiogenic effect of licorice extract depended on the anti-tube formation effect of isoliquiritin (Kobayashi et al., 1995) . On the other hand, as for the estrogen-like activities of glabridin in in vivo and in vitro studies, it was demonstrated that it could modulate vascular injury and atherogenesis. Therefore, it is suggested for the prevention of cardiovascular diseases in post-menopausal women (Somjen et al., 2004b) .

Several immunomodulatory activities have been attributed to glycyrrhizin and glycyrrhetinic acid (Ohuchi et al., 1981; Kobayashi et al., 1993; Zhang et al., 1993; Kondo and Takano, 1994 ; Raphael and Kuttan, 2003) . The same results were seen with lichochalchone A and some analogues which showed immunomodulatory effects (Barfod et al., 2002) .

On the other hand, glycyrrhizin selectively activated extrathymic T cells in the liver and in human T cell Copyright 

Antitumor activity, induced apoptosis by modulating bcl-2 protein expression (Rafi et al., 2000 (Rafi et al., , 2002 Fu et al., 2004) Antitumor promoting activity by preventing TPA to bind to the membrane receptors (Kitagawa et al., 1986; Shibata et al., 1991) Inhibitory effect (Shibata et al., 1991) Antitumor-promoting activity (Kitagawa et al., 1986) Protective effect and prevent chemicalinduced carcinogenicity by inhibition the activation of hepatotoxic metabolites (Chan et al., 2003) Inhibited induction of ACF and colon carcinoma development (Baba et al., 2002; Takahashi et al., 2004) Inhibited epidermal ODC and suppressed DMBA effects (Yamamoto et al., 1991) Induced cell death and promotion of Bax expression (Iwashita, et al., 2000) Antiproliferative activity (Ma et al., 2001) Antiproliferative activity (Maggiolini et al., 2002) Antiproliferative activity (Kanazawa et al., 2003) Inhibited cell growth and decreased cell number, induced apoptosis (Jung et al., 2006) Antiproliferative activity, enhanced expression of p21 CIP1/WAF1 expression (Hsu et al., 2004; Ii et al., 2004) Reduced pulmonary metastasis (Yamazaki et al., 2002) Induced apoptotic cell death by inhibiting the NF-kappaB survival-signaling pathway (Hsu et al., 2005) Antiproliferative effects (Tamir et al., 2000) Inhibited formation, proliferation of total DMBA-DNA adducts in mammary gland (Lin et al., 2001) Cytostatic effect with deregulation cell cycle (Jackson et al., 2002) Method MCF-7 breast, HL-60 leukemia and PC-3 prostate cancer cell lines Ishiwata et al., 1999) . Glycyrrhizin also improved the impaired resistance of thermally injured mice to herpes virus infection (Utsunomiya et al., 1995) . Moreover, glycyrrhetinic acid was an inducer of type 2 antagonistic CD41 T cells in in vivo and in vitro studies (Kobayashi et al., 1993; Utsunomiya et al., 1995; Nakajima et al., 1996) . It improved the resistance of mice infected with LP-BM5 murine leukemia virus (MAIDS) mice to Candida albicans infection (Utsunomiya et al., 2000) . Also, it stimulated macrophagederived NO production, and was able to up-regulate iNOS expression through nuclear factor kB (NF-kB) transactivation in murine macrophages (Jeong and Kim, 2002) . Both of them could induce interferon activity and augment natural killer cell activity and in this study glycyrrhizin was superior to glycyrrhetinic acid in inducing interferon (Abe et al., 1982) . It also has inhibitory effects on TNF-alpha-induced IL-8 production in intestinal epithelial cells (Kang et al., 2005) .

In addition, there are some studies on the immunomodulatory effects of polysaccharide fractions obtained from shoots of G. glabra and hairy roots of G. uralensis in vitro (Nose et al., 1998) . GR-2IIa and GR-2IIb, two isolated acidic polysaccharides of G. uralensis, have shown anticomplementary activity. Also, GR-2IIc had both anticomplementary activity and mitogenic activity (Zhao et al., 1991; Yamada et al., 1992; Kiyohara et al., 1996) . Recently, the haemolytic activities of G. uralensis saponins (GLS) and its adjuvant potentials against ovalbumin (OVA) were established in mice ( Sun and Pan, 2006) .

Glabridin showed an antinephritis effect in the mouse glomerular disease model (Fukai et al. 2003) . Also, glycyrrhizin could ameliorate renal defects in gentamicininduced acute renal failure in rats (Sohn et al., 2003) . Also, the extract of G. radix could protect the kidneys against peroxynitrite (ONOO − )-induced oxidative stress Copyright in vivo through scavenging ONOO − and/or its precursor NO (Yokozawa et al., 2005) .

Sixty nine compounds of Glycyrrhiza phenols showed an inhibitory activity on the growth of Bacillus subtilis H17 and M45 and some of them, such as isoliquiritigenin, were positive in the rec-assay (Fukai et al., 1998) .

Recently in one study, G. radix produced a persistent antitussive effect in the guinea-pig, suggesting that liquiritin apioside, a main antitussive component, plays an important role in the earlier phase, while liquiritigenin and liquiritin play an important role in the late phase (Kamei et al., 2005) . This result is keeping with the previous antitussive effects of licorice.

Glycyrrhitinic acid and its derivatives were shown to inhibit gap junction channels ( Davidson and Baumgarten, 1988) . The inhibitory effects of 18β-glycyrrhetinic acid on gap junction channels of arteriolar smooth muscle, endothelial cells, renal pelvis, ureter and mesenteric small arteries were studied Santicioli and Maggi, 2000; Matchkov et al., 2004) .

Some effects of licorice on the endocrine system in in vitro and in vivo studies are summarized in Table 5 . It seems that this herb acts on the metabolism of steroids with different mechanisms.

In endocrinological studies, glabridin increased the growth of mouse osteoblastic (MC3T3-E1) and human cell lines (Somjen et al., 2004a; Choi, 2005) . The alcohol extract of licorice reduced the glucose levels of genetically diabetic KK-A y mice (Kuroda et al., 2003) .

In addition, dermatological studies showed that three flavonoids of licorice, licuraside, isoliquiritin and licochalcone A, have high potential for studying depigmenting agents by inhibiting tyrosinase (Fu et al., 2005) . The same results were reported for glycyrrhisoflavone and glyasperin C (Kim et al., 2005) .

It was shown that oral licorice in a combination product could heal ulcers as effectively as an H2 blocker (Kassir, 1985; Aly et al., 2005) . Glycyrrhizinic acid, a major component of licorice, has antiulcer properties, it seems by raising the local concentration of prostaglandins that promote mucous secretion and cell proliferation in the stomach, leading to healing of ulcers in experimental studies (Van Marle et al., 1981; Baker, 1994) .

Carbenoxolone, a hemisuccinate derivative of 18βglycyrrhetinic acid, and enoxolone are two chemical synthetic derivatives of licorice which have been used in clinical therapies (Fig. 3) . Enoxolone, an analogue of carbenoxolone, has been used for the treatment of peptic ulcer disease and other GIT disorders, skin disorders, mouth and throat disorders (Sweetman, 2005) . Carbenoxolone has been used for peptic ulcer disease, gastro-oesophageal reflux and also it has been used for the symptomatic management of mouth ulceration as a gel or mouthwash (Sweetman, 2005) .

Licorice root has been identified by the National Cancer Institute as possessing cancer-preventive properties (Craig, 1999 ; Wang and Nixon, 2001) . It has been used among patients with prostate cancer as an ingredient of PC-SPES, a commercially available combination of eight herbs (DiPaola et al., 1998) .

G. glabra extracts showed great antioxidant and free radical scavenging activities in topical formulations and may be used in topical formulations in order to protect the skin against damage caused by free radical and reactive oxygen species (Di Mambro and Fonseca, 2005) . 

In the world, especially in Asia, glycyrrhizic acid is used intravenously for the treatment of chronic hepatitis B and C and its preparation under the name of Stronger Neo-Minophagen C (SNMC) decreased aminotransferase levels in patients with chronic hepatitis in multiple double-blind studies (Van Rossum et al., 1999; Iino et al., 2001; Zhang and Wang, 2002) . It is suggested that glycyrrhizin has a preventive effect on the development of hepatocellular carcinoma (HCC) in patients with HCV-associated chronic hepatitis (Arase et al., 1997; Miyakawa and Iino, 2001) . Licorice has been reported to have a direct hepatoprotective effect (Luper, 1999; Leung et al., 2003) . Glycyrrhizin, its major component, is often used to treat patients with chronic liver damage who do not receive or respond to interferon (IFN) therapy (Okuno et al., 2001) . Stronger Neo-Minophagen C ® (SNMC), containing 2 mg/mL of glycyrrhizin, has been used clinically as an antihepatitis agent (Shibata, 2000) .

G. glabra L. has been used in herbal medicine for skin eruptions, including dermatitis, eczema, pruritus and cysts (Saeedi et al., 2003) . In this section the various studies of licorice on the skin are summarized in Table 6 .

Recently glycyrrhizin treatment has showed protective effects against UVB-irradiated human melanoma cells (Rossi et al., 2005) . Moreover, licorice extract and its active component, glycyrrhizic acid has been described as effective skin whitening effects (Smith, 1999) . The group of Briganti classified liquiritin as a skin turnover accelerator (Briganti et al., 2003) . However, it was suggested that liquiritin causes depigmentation by two mechanisms: first, via melanin dispersion by means of the pyran ring of its flavonoidal nucleus; second the acceleration of epidermal renewal (Amer and Metwalli, 2000) . Concerning the mechanisms of glabridin on melanogenesis and inflammation, it has been shown that it inhibits the tyrosinase activity of melanocytes and as a result, it seems that hydroquinone will be replaced by licorice extract in a new preparation for dermal melasma (Piamphongsant, 1998) . However, in a few cases, allergic dermatitis can develop to oil soluble licorice extracts (Nishioka and Seguchi, 1999) .

Glycyrrhiza root has been shown to decrease circulating levels of testosterone in men and women (Armanini et al., 1999 (Armanini et al., , 2002 Rafi et al., 2002; Armanini et al., 2004) . But it was not able to reduce salivary testosterone in men significantly (Josephs et al., 2001) . Moreover, it induced regular ovulation and pregnancy in infertile hyperandrogenic patients (Yaginuma et al., 1982) .

On the other hand, isoliquiritigenin (ILC), glabrene and glabridin are phytoestrogens. ILC and glabrene can bind to the human estrogen receptor (ER) with higher affinity than glabridin. It was suggested that isoflavenes may serve as natural estrogen agonists in preventing the symptoms and diseases associated with estrogen deficiency (Tamir et al., 2000 (Tamir et al., , 2001 . In some traditional Chinese medicine preparations, the root of G. glabra is used for treatment menopause-related symptoms. But there are no clinical data regarding its safety or efficacy for treating hot flashes (Santoro et al., 2004) .

Moreover, the activity of 11β-HSD-2 potently is blocked in vivo and in vitro by glycyrrhetinic acid by two mechanisms, direct competitive inhibition and pretranslational inhibition (Ferrari et al., 2001) . It seems that this herb acts on the metabolism of steroids with different mechanisms. The consumption of licorice extract and glycyrrhetinic acid could decrease body fat mass in humans and a possible mechanism seems to be by inhibiting 11β-HSD1 at the level of fat cells (Armanini et al., 2005) .

Licorice has been used as a cough-relieving medicinal herb from ancient times. It seems that mucilage present in it or secretion produced under the influence of the active substances covers the oral and throat mucosa soothing its irritability and relieving dry cough (Ody, 2000; Puodziuniene et al., 2005) .

Ammonium glycyrrhizate (from licorice root) is used in toothpastes, mouth rinses and other products for the control of periodontal disease (Goldie, 2005) . The extract of G. glabra in combination with other herbs, such as ImmunoGuard ® , has been effective for the prophylactic management and treatment of patients with Familial Mediterranean Fever (FMF) (Amaryan et al., 2003) .

Commercially, licorice is added to chewing gum, chocolate candy, cigarettes, smoking mixtures, chewing tobacco and snuff as sweetening agents (Tyler et al., 1988; De Klerk et al., 1997) and as a depigmentation Melanogenesis, inflammation (Yokota et al., 1998; Petit and Pierard, 2003; Halder and Richards, 2004) Glycyrrhetinic acid (GA). Dobbins and Saul, 2000; Fraunfelder, 2004 Cardiovascular Torsades de points Eriiksson et al., 1999 tachycardia Cardiac arrest Bannister et al., 1977 Hypertension Olukoga and Donaldson, 2000 Edema De Groot et al., 1988 Shibata, 2000 Endocrine Hypokalemia Nielsen and Pedersen, 1984 ; Olukoga and Davidson, 2000 Bernardi et al., 1994 agent in cosmetics (Nomura et al., 2002) . Also, licorice is frequently employed to mask the taste of bitter drugs such as aloe, quinine and others. The surfactant property of the saponins may also facilitate the absorption of poorly absorbed drugs, such as the anthraquinone glycosides (Tyler et al., 1988) . Some of the products which have glycyrrhizinic acid are summarized in Table 7 ( De Klerk et al., 1997) .

Large amounts of licorice may result in severe hypertension, hypokalemia and other signs of mineralocorticoid excess. This hypertension is caused by decreased 11β-HSD2 activity. This enzyme is responsible for the renal conversion of cortisol to cortisone. Thus, licorice leads to activation of renal mineralocorticoid receptors by cortisol, resulting in a state of apparent mineralocorticoid excess and suppression of the rennin angiotensin system (Conn et al., 1968 , Stewart et al., 1990 Van Uum, 2005) . Some side effects due to the consumption of licorice have been reported by different groups and are summarized in Table 8 . Carmines et al. (2005) reported that adding licorice extract to cigarette tobacco at levels of ≤5% (about 0.269% glycyrrhizic acid) did not significantly alter the toxicity of smoke. Also, in this paper, it was mentioned that licorice is not a teratogen or genotoxic (Carmines et al., 2005) . In another study, the toxicity of licorice extract was shown in the liver of Black molly fish (Radhakrishnan et al., 2005) .

After oral administration, glycyrrhizin is metabolized to glycyrrhetinic acid by intestinal bacteria which contain β-D-glucuronidase (Hattori et al., 1985) . Furthermore, intravenously administered glycyrrhizin is metabolized in the liver by lysosomal β-D-glucuronidase to 3mono-glucuronide glycyrrhetinic acid. This metabolite is excreted with bile into the intestine, where it is metabolized by bacteria into glycyrrhetinic acid, which can be reabsorbed (Akao et al., 1991) (Fig. 4) .

doses of KCl supplementation for weeks are necessary because of the long half-life of glycyrrhetic acid (Van Den Bosch et al., 2005) .

In another study, liquiritin apioside showed a peak plasma concentration 15 min after administration in guinea-pigs, which gradually decreased and was almost undetectable 4 h after administration. Liquiritigenin, an aglycone of liquiritin apioside, appeared in the plasma 2 h after the administration of liquiritin apioside and remained for more than 6 h after administration. The plasma concentration of unchanged liquiritigenin was observed 15 min after administration and then gradually increased for more than 6 h after administration (Kamei et al., 2005) .

Glycyrrhizin, genistein, glycyrrhisoflavone, glicoricone, licofuranone, licopyranocoumarin licocoumarone and other licorice constituents were found to inhibit monoamine oxidase (MAO) in vitro (Hatano et al., 1991b) . However, the clinical significance of this is not known and not all these compounds are found in all species.

Based on the phenolic constituent of licorice sp, they were classified into three types A, B, C:

Type A: roots and rhizomes of G. uralensis containing licopyranocoumarin, glycycoumarin and/or licocoumarone, which were not found in G. glabra and G. inflata. Type B: G. glabra, containing glabridin and glabrene, which were not found in the samples of the other two species. Type C: G. inflata, containing licochalcones A and B, which were not found in the other two species.

Extracts of some licorice specimens of types A, B, and C inhibited 40-56% of xanthine oxidase activity. Extracts of some licorice specimens of types A and B also showed inhibitory effects on monoamine oxidase (44-64%) (Hatano et al., 1991a) .

The extract of G. uralensis showed potent CYP3A4 inhibitory activity (Hu et al., 1999; Budzinski et al., 2000; Tsukamoto et al., 2005) . After bioassay purification, other components such as (3R)-vestitol, 4-hydroxyguaiacol apioglucoside, liquiritigenin 7, 4′-diglucoside, liquiritin apioside showed potent CYP3A4 inhibitory activities among them (Tsukamoto et al., 2005) . Glabridin was also found to inactivate the enzymatic activities of CYP 3A4 and 2B6 and competitively inhibited 2C9 (Kent et al., 2002) .

In other hands, prolonged intake of high LE or G doses may result in accelerated metabolism of coadministered drugs. Daily oral doses of LE or G for 1, 4 or 10 consecutive days in mice, were able significantly to induce hepatic CYP3A-and, to a lesser extent, 2B1-and 1A2dependent activities, as well as 6-beta-(mainly associated to CYP3A), 2-alpha-, 6-alpha-(CYP2A1, 2B1), 7-alpha-, 16-alpha-(CYP2B9) and 16-beta-testosterone hydroxylase (TH) activities. Thus, the induction of cytochrome P450-dependent activities by long-term ingestion of licorice may have clinical consequences for patients taking drugs metabolized by the same CYP enzymes (Paolini et al., 1998) . But, high doses of LE and G could cause significant adverse effects. Thus, it seems that routine licorice consumers under CYP3A induction might therefore be predisposed to associated Other components of the extract could affect the pharmacokinetics of glycyrrhizin (G) and glycyrrhetic acid (GA), a main metabolite of G. After administration of aqueous licorice root extract (LE) to rats and humans, G and GA levels were lower compared with G alone and the pharmacokinetic curves showed significant differences in the areas under the plasma-time curve (AUC), C max , and T max parameters. Also, the data obtained from urine samples confirmed a reduced bioavailability of G present in LE compared with pure G. Interaction between the G constituent and other components in LE during intestinal absorption was mentioned. Thus, modified bioavailability could explain the various clinical adverse effects resulting from the chronic oral administration of G alone as opposed to LE (Cantelli-Forti et al., 1994) . However, it seems that the pharmacokinetics differ in other species. In another study the AUCs of G and GA after oral administration of LE were significantly higher than those after pure G in rabbits and the bioavailabilities of G and GA were significantly better from licorice than from pure G in rabbits, but the presystemic metabolism of pure G in the rabbit is rather different from that in rat, pig and human (Hou et al., 2005) . It was shown that the pharmacokinetics of G is nonlinear. After bolus intravenous administration at a dose of 20, 50, or 100 mg/kg in rat, the decline in the concentration of G in plasma, was generally biexponential at each dose, but the terminal disposition became much slower as the dose was increased. In addition, the apparent total body clearance decreased significantly with increases in the dose. But the apparent distribution volume after intravenous administration was unaffected by the dose (Tsai et al., 1992) . Administration of different oral doses of 18beta-glycyrrhetinic acid (β-GRA) in healthy volunteers showed a biphasic decay of the plasma concentrationtime curve at doses >500 mg. The peak plasma concentration and the AUC increased with increasing β-GRA doses. Urinary elimination of β-GRA and its glucuronides over 24 h was less than 1% of the dose administered. The data based on single dose kinetic analysis revealed that after multiple doses of 1.5 g β-GRA/day, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently (Krahenbuhl et al., 1994) .

Administration intravenously of G to an animal model of liver disease (D-galactosamine-intoxicated (GAL) rat), significantly decreased the apparent volume of distribution (V dss ) and the total body clearance (CL total ) than those in normal rats. When G was administered orally, the AUC, the mean residence time (MRT) and the time to reach the maximum plasma concentration (T max ) for G were higher, but the maximum plasma concentration (C pmax ) in GAL rats was lower than that in normal rats. But, the bioavailability of G was not significantly changed. Also, the AUC for GA, after oral administration of G was higher in GAL rats than in normal rats, although there was no significant difference in MRT or T max , C pmax or the bioavailability for GA between GAL and normal rats. However, the changes in the absorption rate and reduction of the hepatic elimination rates in GAL rats could explain these differences (Wang et al., 1996) . GA has a large volume of distribution, a long biological half-life, and undergoes substantial enterohepatic circulation (Tyler et al., 1988 G. uralensis) in rats (Mu et al., 2006) 

Acetaminophen Increased the excretion of acetaminophen-glucoronide conjugate in rats ( Moon and Kim, 1996) 

Prednisolone Decreased CL, increase AUC and Cp of prednisolone (Chen et al., 1991) GA Hydrocortisone Increase effect of hydrocortisone in mice (Teelucksingh et al., 1990 ) GA Oral contraceptive Hypertension, edema, hypokalemia, increase sensitivity to glycyrrhizin, sensitivity to adverse effects in women is more than in men (Bernardi et al., 1994; De Klerk et al., 1997) Clearance (CL), area under curve (AUC), plasma concentration (Cp), glycyrrhetinic acid (GA).

adverse effects. Furthermore, consumption of licorice is contraindicated during pregnancy and for patients with liver disorders, hypokalemia like those who are taking cardiac glycosides. The aldosterone effects of licorice root may counteract antihypertensive action of prescribed medications (Cassileth and Barazzuol, 2001) . Recently, a direct interaction of glycyrrhetinic acid absorption with sennosides and its derivatives has been studied in humans (Mizuhara et al., 2005) . Some drug interactions of licorice which have been reported are summarized in Table 9 .

In summary, licorice is used throughout the world as a traditional herbal remedy. As for the properties of licorice and its active constituents, it is suggested that their potential roles are evaluated for their effects in the treatment of different kinds of disease such as cancer, atherosclerosis, immunodeficiency, hormone deficiency endocrine and skin diseases. However, it is necessary to carry out further studies to confirm these effects.

Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice

Effect of licorice root on peripheral blood indexes upon vibration exposure

Spectral quality and UV-B stress stimulate glycyrrhizin concentration of Glycyrrhiza uralensis in hydroponic and pot system

Mechanism of anti-inflammatory action of glycyrrhizin: effects on neutrophil functions including reactive oxygen species generation

Hydrolysis of glycyrrhizin to 18 beta-glycyrrhetyl monoglucuronide by lysosomal beta-D-glucuronidase of animal livers

Licorice: A possible antiinflammatory and anti-ulcer drug

Comparative studies of the stereoisomers of glycyrrhetinic acid on anti-inflammatory activities

Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard ® -a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever

Anticonvulsant activity of roots and rhizomes of G. glabra

Topical liquiritin improves melasma

The long term efficacy of glycyrrhizin in chronic hepatitis C patients

Licorice consumption and serum testosterone in healthy man

Reduction of serum testosterone in men by licorice

History of the endocrine effects of licorice

Licorice reduces serum testosterone in healthy women

Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical application

Studies on medicinal plants of Srilanka. Part 14. Toxicity of medicinal herbs

Hepatoprotective effect of Silybum marianum

Glycyrrhiza glabra L. in the rats

Pharmacological study of the anti-inflammatory agent glyderinine

Studies on cancer chemoprevention by traditional folk medicines, XXV. Inhibitory effect of isoliquiritigenin on azoxymethane-induced murine colon aberrant crypt focus formation and carcinogenesis

Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro

Licorice and enzymes other than 11 betahydroxysteroid dehydrogenase: an evolutionary perspective

Cardiac arrest due to liquorice induced hypokalaemia

Chalcones from Chinese liquorice inhibit proliferation of T cells and production of cytokines

The antioxidative effects of the isoflavan glabridin on endogenous constituents of LDL during its oxidation

Structural aspects of the inhibitory effect of glabridin on LDL oxidation

Effects of prolonged ingestion of graded doses of licorice by healthy volunteers

Dihydrostilbene derivatives from Glycyrrhiza glabra leaves

Herbal Medicine: Expanded Commission E Monographs

Chemical and instrumental approaches to treat hyperpigmentation

An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures

Interaction of liquorice on glycyrrhizin pharmacokinetics

Glycyrrhetinic acid, leucocytes and prostaglandins

Toxicologic evaluation of licorice extract as a cigarette ingredient

Herbal products and other supplements problems of special relevance to surgery

Inhibition of glycyrrhizic acid on aflatoxin B1-induced cytotoxicity in hepatoma cells

Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania

Antileishmanial activity of licochalcone A in mice infected with Leishmania major and in hamsters infected with Leishmania donovani

Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone

Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection

Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones

The licorice root derived isoflavan glabridin increases the function of osteoblastic MC3T3-E1 cells

Antimalarial natural products

An antileishmanial chalcone from Chinese licorice roots

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

Treatment of irritant and allergic contact dermatitis

Licking latency with licorice

Licorice-induced pseudoaldosteronism, hypertension, hypokalemia, aldosteronopenia, and suppressed plasma renin activity

Health-promoting properties of common herbs

Inhibition of hepatitis A virus replication in vitro by antiviral compounds

Glycyrrhizic acid alters Kaposi sarcoma-associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes

Ethnobotanical survey of medicinal plants in northern Israel

Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communication. Structure-activity relationships

Improvement of selectivity and sensitivity by column switching in the determination of glycyrrhizin and glycyrrhetic acid in human plasma by high-performance liquid chromatography

Hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum

Anti-HIV aromatic compounds from higher plants

Memory enhancing activity of Glycyrrhiza glabra in mice

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

Assays of physical stability and antioxidant activity of a topical formulation added with different plant extracts

Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer

Transient visual loss after licorice ingestion

Life-threatening ventricular tachycardia due to liquorice-induced hypokalemia

The effect of dry cleared extract from licorice roots on the learning of ovariectomized rats

In vivo 11β-HSD-2 activity variability, salt-sensitivity, and effect of licorice

On the mechanism of mitochondrial permeability transition induction by glycyrrhetinic acid

Identification of glycyrrhizin as a thrombin inhibitor

Perspective ocular side effects from herbal medicines and nutritional supplements

Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells

Isolation and identification of flavonoids in licorice and a study of their inhibitory effects on tyrosinase

Herb-drug interactions: Review and assessment of report reliability

Licorice extract and its major polyphenol glabridin protect low-density lipoprotein against lipid peroxidation: in vitro and ex vivo studies in humans and in atherosclerotic apolipoprotein E-deficient mice

Traditional medicine in Turkey VII. Folk medicine in middle and regions

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

Anti-Helicobacter pylori flavonoids from licorice extract

Antimicrobial activity of licorice flavonoids against methicillin-resistant Staphylococcus aureus

Preliminary evaluation of antinephritis and radical scavenging activities of glabridin from Glycyrrhiza glabra

Inhibition by licochalcone A, a novel flavonoid isolated from liquorice root, of IL-1β-induced PGE 2 production in human skin fibroblasts

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

Antioxidants in oral health care: making the connection

Nature's own pharmacy: The diabetes perspective

Hypokalemic myopathy with myoglobinuria associated with licorice ingestion

Licorice compounds glycyrrhizin and 18β-glycyrrhetinic acid are potent modulators of bile acid-induced cytotoxicity in rat hepatocytes

Topical agents used in the management of hyperpigmentation

Antioxidative plant constituents

Antioxidative and superoxide scavenging activities of retrochalchones in Glycyrrhiza inflata

Protection of mitochondrial functions against oxidative stresses by isoflavans from Glycyrrhiza glabra

Minor flavonoids from licorice

Phenolic constituents of licorice. IV. Correlation of phenolic constituents and licorice specimens from various sources, and inhibitory effects of licorice extracts on xanthine oxidase and monoamine oxidase

Phenolic constituents of licorice. III. Structures of glicoricone and licofuranone, and inhibitory effects of licorice constituents on monoamine oxidase

Effects of tannins and related polyphenols on methicillin-resistant Staphylococcus aureus

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

Anti-human immunodeficiency virus phenolics from licorice

Metabolism of glycyrrhizin by human intestinal flora. II. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds

Seasonal variation of glycyrrhizin and isoliquiritigenin glycosides in the root of Glycyrrhiza glabra L

Antibacterial compounds from Glycyrrhiza uralensis

Anticonvulsant, sedative and muscle relaxant effects of carbenoxolone in mice

The effects of carbenoxolone, a semisynthetic derivative of glycyrrhizinic acid, on peripheral and central ischemia-reperfusion injuries in the skeletal muscle and hippocampus of rats

The effects of carbenoxolone on spatial learning in the Morris water maze task in rats

Profound difference of metabolic pharmacokinetics between pure glycyrrhizin and glycyrrhizin in liquorice decoction

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

Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells

The induction of liver microsomal cytochrome P450 by Glycyrrhiza uralensis and glycyrrhetinic acid in mice

Selective inhibition of human type 1 11β-hydroxysteroid dehydrogenase by synthetic steroids and xenobiotics

Induction of cell cycle arrest and p21 CIP1/WAF1 expression in human lung cancer cells by isoliquiritigenin

Therapeutic effects of stronger Neo-Minophagen C at different doses on chronic hepatitis and liver cirrhosis

Modulation by glycyrrhetinic acid derivatives of TPA-induced mouse ear oedema

Fas-mediated apoptosis is enhanced by glycyrrhizin without alteration of caspase-3-like activity

Mechanism of inhibitory effect of glycyrrhizin on replication of human immunodeficiency virus (HIV)

Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells

Dibenzoylmethane induces cell cycle deregulation in human prostate cancer cells

Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues

In vitro antiplasmodial activity of Central American medicinal plants

Induction of inducible nitric oxide synthase expression by 18β-glycyrrhetinic acid in macrophages

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 (Glycyrrhiza uralensis roots) and ameliorative effects of glycyrin on genetically diabetic KK-A y mice

The effects of the licorice derivative, glycyrrhetinic acid, on hepatic 3 alpha-and 3 betahydroxysteroid dehydrogenases and 5 alpha-and 5 beta-reductase pathways of metabolism of aldosterone in male rats

Plants and animals used for fertility regulation in Korea

Transcriptional regulation of fosl-1 by licorice in rat Clone 9 cells

Two new compounds from Glycyrrhiza glabra

Inhibition by dietary dibenzoylmethane of mammary gland proliferation, formation of DMBA-DNA adducts in mammary glands, and mammary tumorigenesis in Sencar mice

The effects of pretreatment with glycyrrhizin and glycyrrhetinic acid on the retrorsineinduced hepatotoxicity in rats

Mechanism of action of glycyrrhizic acid in inhibition of Epstein-Barr virus replication in vitro

A review of plants used in the treatment of liver disease: Part Two

Apoptosis induced by isoliquiritigenin in human gastric cancer MGC-803 cells

Glycyrrhetinic acid and potentiation of hydrocortisone activity in skin

Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells

Junctional and nonjunctional effects of heptanol and glycyrrhetinic acid derivates in rat mesenteric small arteries

Antithrombotic effect of glycyrrhizin, a plant-derived thrombin inhibitor

Toward prevention of hepatocellular carcinoma developing in chronic hepatitis C

The influence of the sennosides on absorption of glycyrrhetic acid in rats

Licorice inhibits corticosteroid 11β-dehydrogenase of rat kidney and liver: in vivo and in vitro studies

Effect of Glycyrrhiza glabra roots and glycyrrizin on the glucoronidation in rats

Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate PXR and increase warfarin clearance in rats

Small scale rat hepatocyte primary culture with applications for screening hepatoprotective substances

New lactones in liquorice (Glycyrrhiza glabra L.)

The protective effect of glycyrrhizin against injury of the liver caused by ischemia-reperfusion

In vitro induction of anti-type 2 T cells by glycyrrhizin

Enzyme leakage due to change of membrane permeability of primary cultured rat hepatocytes treated with various hepatotoxins and its prevention by glycyrrhizin

Life-threatening hypokalaemia caused by liquorice ingestion

Contact allergy due to oil soluble licorice extracts in cosmetics products

Aphrodisiac effect of indigenous drugs -a myth or reality?

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

A comparison of the antihepatotoxic activity between glycyrrhizin and glycyrrhetinic acid

Activation of macrophages by crude polysaccharide fractions obtained from shoots of Glycyrrhiza glabra and hairy roots of Glycyrrhiza uralensis

Effect of glycyrrhizin in children with liver dysfunction associated with cytomegalovirus infection

The Complete Guide Medicinal Herbal. Dorling Kindersley: London

Inhibition of serotonin re-uptake by licorice constituents

Changes in succinate dehydrogenase activity in various parts of the brain during combined exposure to vibration and licorice root

Glycyrrhizin inhibits prostaglandin E2 production by activated peritoneal macrophages from rats

Chemoprevention of hepatocellular carcinoma: concept, progress and perspectives

Liquorice and its health implications

Efficacy of four medicinally important plant extracts (crude) against pathogenic bacteria

Apparent mineralocorticoid excess syndrome: an overview

Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases

Search for natural products which affect cyclooxygenase-2

Skin-lightening products revisited

Treatment of melasma: a review with personal experience

Glycyrrhizic acid inhibits virus growth and inactivates virus particles

Development of cough-relieving herbal teas

Effect of licorice (Glycyhrriza glabra Linn.), a skin-whitening agent on Black molly (Poecilia latipinnaa)

Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid

Novel polyphenol molecule isolated from licorice root (Glycyrrhiza glabra) induces apoptosis, G2/M cell cycle arrest, and Bcl-2 phosphorylation in tumor cell lines

Analysis of some herbal plants from India used in the control of mellitus by NAA and AAS techniques

Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system

Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidaseinduced cell-mediated oxidation of low density lipoprotein: a possible role for protein kinase C

Increased macrophage glutathione content reduces cell-mediated oxidation of LDL and atherosclerosis in apolipoprotein E-deficient mice

Effects of glycyrrhizin on UVB-irradiated melanoma cells

Screening of plants from the southeast of Iran for antimicrobial

The treatment of atopic dermatitis with licorice gel

Inhibitory effect of glycyrrhetinic acid on testosterone production in rat gonads

Glycyrrhetinic acid-induced permeability transition in rat liver mitochondria

Effect of 18 beta-glycyrrhetinic acid on electromechanical coupling in the guinea-pig renal pelvis and ureter

Treatment of menopauseassociated vasomotor symptoms: position statement of menopause

Therapeutic basis of glycyrrhizin on chronic hepatitis B

Potential regulation of inflammation in the lung by local metabolism of hydrocortisone

Aphthus ulcerations

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

A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice

Inhibitory effects of lichochalcone A isolated from Glycyrrhiza inflata root on inflammatory ear edema and tumor promotion in mice

Effect of glycyrrhizin on lysis of hepatocyte membranes induced by anti-liver cell membrane antibody

Glycyrrhizin (licorice)-induced hypokalemic myopathy: report of 2 cases and review of the literature

Pharmaco-therapeutics of dasemani drugs

The effects of topical L (+) lactic acid and ascorbic acid on skin whitening

Protective effects of glycyrrhizin on gentamicin-induced acute renal failure in rats

Estrogenic activity of glabridin and glabrene from licorice roots on human osteoblasts and prepubertal rat skeletal tissues

Estrogenlike activity of licorice root constituents: glabridin and glabrene, in vascular tissues in vitro and in vivo

Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man

Birth outcome in relation to licorice consumption during pregnancy

Immunological adjuvant effect of Glycyrrhiza uralensis saponins on the immune responses to ovalbumin in mice

Effects of glycyrrhizin and glycyrrhetinic acid on production of O 2 − , H 2 O 2 by macrophages

Martindale: The Complete Drug Reference

Effects of glycyrrhizin on hepatitis B surface antigen: a biochemical and morphological study

Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development

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

Estrogen-like activity of glabrene and other constituents isolated from licorice root

Anti-platelet action of isoliquiritigenin, an aldose reductase inhibitor in licorice

Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid

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

Pharmacokinetics of glycyrrhizin after intravenous administration to rats

Synthesis and inhibitory effect of novel glycyrrhetinic acid derivatives on IL-1b-induced prostaglandin E 2 production in normal human dermal fibroblasts

CYP3A4 inhibitors isolated from licorice

Pharmacognosy, 9th edn

Glycyrrhizin (20b-carboxy-11-oxo-30-norolean-12-en-3b-yl-2-O-b-D-glucopyranuronosyl-a-D-glucopyranosiduronic acid) improves the resistance of thermally injured mice to opportunistic infection of herpes simplex virus type 1

Glycyrrhizin improves the resistance of MAIDS mice to opportunistic infection of Candida albicans through the modulation of MAIDS-associated Type 2 T Cell responses

Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus

Severe hypokalaemic paralysis and rhabdomyolysis due to ingestion of liquorice

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

Review article: Glycyrrhizin as a potential treatment for chronic hepatitis C

Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial

Liquorice and hypertension

Study of saponins from Glycyrrhiza glabra root

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

11 beta-Hydroxysteroid dehydrogenase and enzyme-mediated receptor protection: life after liquorice?

Licorice and cancer

Pharmacokinetics of glycyrrhizin in rats with D-galactosamineinduced hepatic disease

Liquorice. In Potter's Cyclopedia of Herbal Medicines. C W Daniels: Saffron Walden

Effect of traditional herbal medicine on serum testosterone levels and its induction of regular ovulation in hyperandrogenic and oligomenorrheic women

Mitogenic and complement activating activities of the herbal component of Juzen-Taiho-To

The potent antitumor-promoting agent isoliquiritigenin

Blockade by 18β-glycyrrhetinic acid of intercellular electrical coupling in guinea-pig arterioles

Isoliquiritigenin suppresses pulmonary metastasis of mouse renal cell carcinoma

Botanical medicine for cystitis

The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation

Glycyrrhizae Radix attenuates peroxynitrite-induced renal oxidative damage through inhibition of protein nitration

Cytotoxic allyl retrochalcone from the roots of Glycyrrhiza inflate

Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta

Critical roles of platelets in lipopolysaccharide-induced lethality: effects of glycyrrhizin and possible strategy for acute respiratory distress syndrome

The cardioprotective action of 18-dehydroglycyrrhetic acid in experimental myocardial damage

The antileishmanial agent licochalcone A interferes with the function of parasite mitochondria

Protective effects of isoliquiritigenin in transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats

Glycyrrhizin as a promoter of the late signal transduction of interleukin-2 production by splenic lymhocytes

Randomized clinical trial with two doses (100 and 40 ml) of Stronger Neo-Minophagen C in Chinese patients with chronic hepatitis B

Heterogeneity and characterisation of mitogenic and anti-complementary pectic polysaccharides from the roots of Glycyrrhiza uralensis Fisch et D.C