Review Article

Glycyrrhiza glabra: Medicine over the millennium Sanjai Saxena Department of Biotechnology and Environmental Sciences Thapar Institute of Engineering and Technology, Patiala 147 004, Punjab, India E-mail: [email protected], [email protected] Received 9 December 2004; Revised 24 March 2005 Abstract

Glycyrrhiza glabra Linn. is an age-old plant used in traditional medicine across the globe for its ethnopharmacological values to cure varieties of ailments from simple cough to hepatitis to more complex like SARS and cancer. The present paper is an effort to highlight the role of a few major constituents of this plant, which have multifaceted pharmacological actions and could be used as templates for designing new pharmacophores using modern chemical and bioanalytical tools. Keywords: Bioactive constituents, Glycyrrhiza glabra, Licorice/, Pharmacophores, Glycyrrhizin. IPC code; Int. cl.7 ⎯ A61K7/00, A61K 35/78, A61P 1/04, A61P 1/16, A61P 11/00, A61P 31/00, A61P 35/00 Liquorice roots Introduction Glycyrrhiza glabra Linn. roots are used for the treatment of upper (Family: Fabaceae) is a medicinal plant respiratory tract ailments including The widespread use of herbal found in Asia, the Mediterranean and parts coughs, hoarseness, sore throat and remedies and healthcare preparations, as of southern Europe. Commonly known as bronchitis. Ayurveda considers licorice to those described in ancient texts such as Licorice/Liquorice, Sweet wood, be a “rasayana” with implicated use in the Vedas, the Bible, and those obtained Mulahatti and Yastimadhu. The treatment of respiratory and digestive from traditional/folklore practices, has underground unpeeled or peeled stems or disorders. It is also considered as an anti- been traced to the occurrence of natural stress and anabolic agent. Licorice the products with medicinal properties. Plants most prescribed herb after Ginseng in synthesize and accumulate a variety of China is used for ailments related to compounds, which provide protection to spleen, liver and kidney. Japanese use the the plant and are useful to humans as herb as an antiviral agent5. medicinal agents. In most developing The present review highlights the countries the use of medicinal plants has contribution of G. glabra in been observed as a normative basis for complementary and modern medicine for maintenance of good health. the development of new drugs. There is a Approximately 80% world population co-relation established between the relies on herbal medicines as over the bioactivity of the herb and the bioactive counter (OTC) herbal formulations and compounds responsible under separate proprietary herbal drugs 1,2. Industrialized headings for facilitating the readers as per societies are involved in extraction of their research interests. The paper also bioactive constituents from medicinal deals with use of licorice in polyherbal plants and use them directly or indirectly formulations as a variety of them have been as new drugs 3, 4. Glycyrrhiza glabra plant evaluated during clinical studies6.

358 Natural Product Radiance Review Article

Bioactive constituents

Liquorice has Glycyrrhizin as the major water-soluble constituent responsible for its sweet taste. Glycyrrhizin is a triterpenoid saponin that is present within a range of 2-14% in different species. The Glycyrrhizin content varies between 5.5-6.4% on weight basis7, 3-3.5% in Radix glycyrrhizae8. Other phytochemicals present in liquorice are: Licoisoflavanone Glycyrrhizin , Liquiritin (), , Isoliquiritin (Chalcones), , Glicoricone, Glisoflavone, Isoangustone A (); Glycyrrhizoflavanone, Glyasperin F, Licoisoflavanone (Isoflavanones); Glyasperin C, Glyasperin D, , Licoricidin (Isoflavans); Glycocoumarins, Lipocoumarins, Glycyrin (3-arylcoumarins) Glabridin Isoliquiritigenin and others (Licocoumarone, Licoriphenone, Isoglycryol)9.

Pharmacological and other properties

Traditionally the plant has been recommended as a prophylaxis for gastric and duodenal ulcers and dyspepsia as an anti-inflammatory agent during allergenic Liquiritigenin Glycyrin reactions9. In folk medicine, it is used as a laxative, emmenagogue, contraceptive, galactagogue, anti-asthmatic drug and antiviral agent. The voluminous studies carried out by ethnobotanists, phytochemists and experimental pharmacologists on its bioactivities suggest that the plant may be a source of new drugs and therapeutic formulations for the treatment of a variety of diseases and ailments (Table 1) could Glycyrrhetinic acid be manufactured. Summary of various activities is given here:

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Antitussive and demulcent from licorice roots exerts the anti- like glabridin, glabrene. licochalcone A, ulcerogenic effect by inhibiting the licoricidin and licoisoflavone B exhibited The liquorice powder and extract secretion of gastrin14. Carbenoxolone in vitro activity against the growth of was found to be useful for the treatment and Pirenzepine were found to have a Clarithromycin and Amoxicillin resistant of sore throat, cough and bronchial similar, but rather limited, efficacy in H. pyroli19. Further the mechanism of catarrh. It is antitussive and expectorant speeding the healing of chronic gastric antimicrobial activity of licochalcone A loosening and helping to expel congestion ulcers. Both the drugs differed with is via inhibition of NADH cytochrome c in the upper respiratory tract as it respect to tolerability. Some antiulcer reductase in the bacterial respiratory accelerates tracheal mucus secretion10. compounds like glycyrin, , electron transport chain20. G. glabra The demulcent action is attributed to glyasperin D, 6,8-diprenylorobol, extracts have been evaluated and glycyrrhizin. It has been recently found that gancaonin I, dihydrilicoisoflavone A and implicated in oral mouth washes against Liquiritin apioside is an active compound gancaonol B possess weaker anti- oral pathogens and oral candidal present in the methanolic extract of Helicobacter pyroli activity which may thrush21,22. A variety of compounds isolated liquorice. The compound inhibits be useful chemoprotective agents for from Glycyrrhiza include glabridin, capsaicin-induced cough11. peptic ulcers in H. pyroli infected gabrin, glabrol, glabrene, hispaglabridin individuals15. A, hispaglabridin B; 40-methylglabridin Thrombin inhibitor and 3-hydroxyglabrol have exhibited Antimicrobial potential in vitro antimicrobial Glycyrrhizin, an already known activity 23, 24. Glycyrrhizinic acids have been anti-inflammatory compound, has also Multi-drug resistant micro- used as a cure to atopic dermatitis, been found as the first plant based organisms pose a serious global threat in pruritis and cysts due to parasitic inhibitor of thrombin. It prolonged the clinical medicine today due to the rapid infestations of skin25. thrombin and fibrinogen clotting time and spread as well as chronic infections caused increased plasma recalcification duration. by them. Each species of the genus Antiviral The thrombin induced platelet aggregation Glycyrrhiza Linn. is characterized by was found to be inhibited by the isoprenoid phenols, which have selective There is an ever increasing action of glycyrrhizin but Platelet antimicrobial spectrum. Glabridin, database of natural products in treating Aggregating Factor (PAF) or Collagen glabrene and glabrol are the main phenols and preventing medical problems. Plant induced agglutination was not affected by present in purified chemicals have been subjected glycyrrhizin 12,13. G. glabra, licoricidin, licorisoflavan in to extensive screening but a few studies G. uralensis Fisch., licochalcone A in have been initiated on crude plant Antiulcerative G. inflata Batal. and G. eurycarpa materials and herbal preparations to be P C Li and Glyasperin E in G. aspera used in healthcare systems. Glycyrrhizin Licorice has been used as an Pallas. Glicophenone and glicoiso- has a prominent antiviral activity, as it does antiulcerative since early 1970’s. The present in G. glabra are two not allow the virus cell binding26,27,28. extracted glycyrrhizin from licorice is new phenolic compounds having potential β-Glycyrrhizic acid has been found to referred to as Deglycyrrhizinated licorice activity to control Methicillin resistant inhibit HIV-1 reproduction in MT-4 (DGL) and is generally used for the Staphylococcus aureus (MRSA) 16,17. cells29, 30. Replications of flaviviruses like treatment of ulcers. Carbenoxolon Effective Minimal Inhibitory the Japanese encephalitis virus, yellow sodium, hemisuccinate sodium and Concentration (MIC) of licochalcone A is fever virus were inhibited by high glycyrrhetinic acid (GA) isolated from 16µg/ml for MRSA and 3µg/ml for food non-cytotoxic concentrations. Recently liquorice have been used to treat a variety borne pathogens like Clostridium spp. antiviral activities of ribavirin, of peptic ulcers. Fraction FM-100 isolated and Bacillus subtilis18. Some compounds 6-azauridine, pyraziofurin, mycophenolic

360 Natural Product Radiance Review Article - - + + - + - -- Glycerin Liquiritigenin + ------+ + Glycyrrhiza glabra + ------+++ Licochalcones Glabrene ---- - ++ + ----- + --- Phytochemicals + - ++ ++ - + -- acid + - + ------+ ------lycyrrhizin Glabridin Glycyrrhetinic Isoliquiritigenin Table 1 : Pharmacological activity of major chemical components Table ------AntiviralAntioxidant Antidiabetic + Hepatoprotective + + AnticancerDrug- delivery + + inhibitorPhytoestrogens Immunostimulating + Activity G Antimicrobial + + Antitussive/Demulcent Antithrombin + + Antiulcer + Indicates the presence of activity compound; - indicates not reported

Vol 4(5) September-October 2005 361 Review Article acid and glycyrrhizin against two clinical Antidiabetic Hepatoprotective isolates of SARS (Severe Acute Respiratory Syndrome) virus (FFM-1 and FFM-2) from Type 2 (non- insulin dependent) Chronic hepatitis (viral as well patients with SARS, admitted to clinical diabetes mellitus, an insulin resistant as non-viral) is a slowly progressive liver center of Frankfurt University, Germany syndrome, is a growing heath concern in disease that may evolve into cirrhosis with were evaluated and it was observed that the modern society. Peroxisome proliferation its potential complications of liver failure Glycyrrhizin was the most effective in activated receptors (PPAR’s) are ligand or hepatocellular carcinoma. Current controlling viral replication and could be dependent transcriptional factors therapy with the alpha-interferon is used as a prophylactic measure28. regulating the expression of a group of directed as viral clearance, but sustained Glycyrrhizin has been previously used to genes that play an important role in glucose response is only achieved in 20-40% of treat patients suffering from HIV-1 and and lipid metabolism. The PPAR receptors patients without cirrhosis and is less than chronic hepatitis C virus27,29,31. Thus, it are classified as PPAR-α, PPAR-γ and 20% in patients with cirrhosis who have would not be out of place to work on the PPAR-δ. The PPAR-α is found in liver, greatest need of therapy. In Japan chemistry of Glycyrrhizin and make it an muscle and kidney. PPAR-γ is associated glycyrrhizin has been used for more than efficient pharmacophores for use as an with adipose tissue, adrenals and small 60 years as treatment for chronic hepatitis antiviral drug. intestine whereas PPAR-δ is expressed under the name of Stronger Neo- ubiquitously. PPAR-γ serves as a Minophagen C (SNMC) clinically as an Antioxidant and predominant target for insulin sensitizing anti-allergic and antihepatitis agent38. Antiinflammatory drugs like Pioglitazone and Roziglitazone. Glycyrrhizin induced a significant Ethyl acetate extract of licorice using GAL- reduction in serum aminotransferases and Glycyrrhiza root powder has 4-PPAR-γ chimera assay, exhibited a improved the liver histology when exhibited a marked hepatoprotective significant PPAR-γ binding activity which compared with the placebo. It has also action by antioxidant activity of liver was attributed to six phenolic compounds, been implicated that long-term usage of against ascorbate dependent oxidation of viz. dehydroglyasperin, glyasperin B, glycyrrhizin prevents development of endogenous polyenic lipids in rat liver32. glyasperin D, glycycoumarin, glycyrin, hepatocellular carcinoma in chronic A variety of phytochemicals present in root glycrol and isolglycyrol36. Pioglitazone and hepatitis C. In vitro studies have extracts of Glycyrrhiza exhibit a potential Glycyrin were found to suppress the indicated that glycyrrhizin modifies the antioxidant activity. Licochalcones B and increased blood glucose level in mice after intracellular transport and suppresses D exhibit a potential activity by inhibiting sucrose loading during the oral sucrose hepatitis B virus (HBV) surface antigen the microsomal lipid peroxidation. tolerance test. Pioglitazone, a potent (HbsAg)39,40. It has been found that 18β- Retrochalcones exhibit mitochondria PPAR-γ agonist ameliorated the insulin glycyrrhetinic acid (GA), an aglycone of lipid peroxidation and prevent red blood resistance and type-2 diabetes mellitus. glycyrrhizin decreases the expression of corpuscles from oxidative hemolysis. Similarly glycyrin also exhibited a potent P450 E1 thereby protecting the liver41. GA Isoflavones like glabridin, hispaglabridin PPAR-γ ligand binding activity and also prevents the oxidative and hepatic A and 3’-hydroxy-4-O-methylglabridin therefore reduces the blood glucose level damage caused by aflatoxins by increasing present in Glycyrrhiza were found to have in knockout diabetic mice (KK- Ay). This the CYP1A1 and Glutathione-S-transferase a very potential antioxidant activity NADH finding is of much significance as licorice (GST) activities and may also contribute dependent peroxidation injury 33,34. More has also been traditionally used as an to anti-carcinogenic activity by metabolic recently dehydrostilbene derivatives like artificial sweetening agent and could be deactivation of the hepatotoxin42. It has α, α-Dihydro-3, 5,4- trihydroxy-4, helpful in insulin resistance syndrome also been experimentally investigated that 5- diiodopentenylstilbene have been prevalent in the modern society. Glycyrrhizin Glycyrrhizin and its analogues have a isolated and found to possess antioxidant has also exhibited antidiabetic activity in mitogenic effect via epidermal growth activity35. non-insulin dependent diabetic model37. factor receptors subsequently stimulating

362 Natural Product Radiance Review Article the MAP (Mitogen Activated Protein) This mechanism could serve as a model convulsant activity against pentylene kinase pathway to induce hepatocyte DNA for development of new chemo-protective tetrazol (PTZ) and lithium pilocarpine synthesis and proliferation43. agents46. induced seizures in mice52. A variety of plant extracts contain compounds, which Anticancer Drug delivery agent have activity similar to ovarian hormones and commonly referred to as a Herbal therapies are being Transdermal delivery of drugs is . There is an increasing looked at with much hope to combat an attractive proposition as it has several demand for phytoestrogens as these have cancers despite little understanding of the advantages over the intravenous or oral beneficial effects mimicking the critical biological diversity underneath. administration due to sensitivity of drugs. benefits of but avoiding the G. glabra extract has been used in The principal barrier is the stratum deleterious effects on breast and uterus. herbal formulations for combating cancers corneum, the outermost layer of the skin The licorice extract and its major isoflavan like PC-SPES, a polyherbal composition comprising keratin rich cells embedded Glabridin act as (ER) used for prostrate cancer. The licorice in multiple layers. A common or simple agonist under in vitro and in vivo extract induced the Bcl2 phosphorylation approach would be to enhance the conditions. The enzyme creatine kinase and G2/M cycle arrest in tumour cell lines permeability of the skin by use of is a biomarker for estrogen responsive as done by clinically used anti-microtubule penetration enhancers or accelerators, genes. Glabrene and isoliquiritigenin have agent Paclitaxel. 1-(2,4- which could induce a reversible a higher affinity for human ER as dihydroxyphenyl)-3-hydoxy-3-(4’- permeability of stratum corneum. It compared to glabridin53. The common hydroxyphenyl)1-propanone( β-hydroxy- has been found that glycyrrhizin extracted finding during premenstrual syndrome DHP) was identified in the licorice extract, from Glycyrrhiza glabra var. (PMS) is the increased ratio of estrogen which induced Bcl2 phosphorylation in glandulifera (roots) enhanced the to progesterone ratio. Liquorice is breast and prostate tumour cells, G2/M percutaneous absorption of diclofenac believed to beneficial during PMS by cell cycle arrest, apoptosis demonstrated sodium using excised abdominal rat skin. reducing the estrogen level and increases by Annexin V and TUNEL assay, decreased The results showed that the efficiency of the progesterone level54. Estrogen and cell viability demonstrated by tetrazolium glycyrrhizin as an enhancer agent is greater progestrin inhibit serotonin re-uptake (MTT) assay, and altered microtubule in gel formulations than in the emulsions. through allosteric interaction with the structure44. 70% Methanol soluble The enhancer with the concentration of serotonin transporter (SERT) in a non- fraction of licorice acetone extract was 0.1%w/w in gel increased diclofenac genomic mechanism. Reduction or found to induce apoptosis in human sodium flux value to tenfold compared blocking of serotonin uptake at synapse monoblastic leukaemia U937 cells. The with the control gel47. Liquiritigenin and helps in alleviation of the depression. compound was identified to be davidigenin have also been reported to be HEK-293 cells have demonstrated that the licocoumarone also responsible for drug delivery agents as they have good isoflavans glabridin and 4′-O-methylglabridin antioxidant and antimicrobial activity45. transepithelial flux through human (4′-OMeG) and the glabrene Activator protein-1 (AP-1) is a nuclear intestinal epithelial cell lines (Caco-2)48. inhibited serotinin re-uptake, whereas transcription factor. Blocking of tumour resorcinol, the isoflavan 2′-O-methylglabridin promoter induced AP-1 activity could be Other pharmacological activities (2′-OMeG) and the isoflavones genistein used to arrest the induced cellular and were inactive in reducing the transformation. It was found that The phytochemicals present in serotonin re-uptake. Thus, the extracts and Glycyrrhizin induced AP-1 activity in Glycyrrhiza sp. are subjected to their phytochemicals could serve as untreated cells whereas inhibited TPA (12- different screens for newer phytoestrogens to ameliorate mild to O-tetradecanoylphorbal-13-acetate) pharmacological activities. The ethanolic moderate depression in pre- and post- induced AP-1 activity in TPA treated cells. extract of Glycyrrhiza exhibited anti- menopausal women by affecting the

Vol 4(5) September-October 2005 363 Review Article serotonergic systems blocking serotonin modifier for immunochemotherapeutic antioxidant, antiviral of the re-uptake55. usefulness by macrophageal expression of phytochemicals present in Glycyrrhiza Radiation therapy has a lot of NO production64. extracts there is a flip side too. Prolonged side effects during the oncological use of glycyrrhiza leads to treatment. Compounds, which can reduce Cosmeceutical –Tyrosinase pseudoaldosteronism65, 66, hypertension67,68 the radiation-induced side effects, are inhibition and hyperkalemia69,70. Liquorice extract being sought and are referred to as and glycyrrhizin have also been reported radioprotective agents. Liquorice extract The synthesis of is under to induce changes in Cytochrome P450 has been found to be radioprotective to the metabolism of aromatic amino acids linked activities resulting in accelerated gamma radiation by preventing lipid that is predominantly regulated by the metabolism of co-administered drugs and peroxidation in rat liver microsome and enzyme Tyrosinase via DOPA. Hyper adverse effects due to change in protect the plasmid DNA from radiation pigmentation is due to excess of melanin cytochrome profiles such as toxicity/ induced strand breaks56. It is implicated biosynthesis. A variety of natural cytotoxicity71. to be anti-mutagenic against Ethylmethane compounds have been used as a sunscreen sulfonate (EMS)57 and prevented DNA agents like the Para-aminobenzoic acid Future approaches damage induced by benzo-α- pyrene58. The (PABA), Vitamin C and kojic acid in licorice extract is not only antidiabetic in cosmeceutical and medicinal treatments The vast range of biological nature but is also used extensively as an but their instability has restricted their effects like antiinflammatory, antiallergic, artificial sweetener and flavour enhancer efficient use. Glabrene is a unique antioxidant, antiviral of the in Japan and USA and called as EMLE compound possessing not only inhabiting phytochemicals present in extracts has (enzymatically modified liquid extract). melanogenesis but also anti- inflammatory been of immense importance in The major components of EMLE again in nature49. Glabrene specifically inhibits phytotherapeutics. Thus, there is an happens to be glycyrrhitinic acid, liquiritic the T1 and T3 tyrosinase isoenzyme activity immense need to modify the natural acid and glycyrrhizin59. and, therefore, Isoliquiritigenin and glycyrrhizin to reduce these side effects Liquorice has been widely used glabrene may serve as skin lightening agent thereby generating the advanced versions in immunomodulating preparations60. for the medicinal and cosmeceutical of the bioactive compounds to be used as Autoimmune diseases have an elevated purposes50. Glycyrrhizin and glycyrrhetinic drugs in future. High throughput methods level of immune complexes (IC). acid (GA) have been found to have a help in generating newer versions of a or immunosuppressive drugs generally significant inhibitory effect on natural product template and generate a perform the treatment of these disorders melanogenesis. Glycyrrhetinic acid as library of compounds or analogs, which have severe side effects. Licorice root stearyl glycyrrhetinate is being used as a could be further screened for a particular extracts have been widely used in Kampo sun care and sunscreen agent. A synthetic activity, safety and toxicology. The medicines; studies have indicated that derivative of GA has been found to screening for a particular activity can be glycyrrhizin present in licorice extracts have a prominent inhibitory potential to achieved using automated high throughput modulates the clearance of IC under the melanogenesis. However, there is a assay system to arrive to a “lead” molecule state of dysfunction61. Glycyrrhizin also need to establish the toxicological suitable for the development into a new restores the impaired interleukin safety of the analog of GA for skin drug72. Glycyrrhizin, glycyrrhetinic acid, IL-2 production in the thermally applications51. glabridin and isoliquiritigenin hold a injured mice62, 63. Nitric oxide (NO) is a Toxic and side effects of strong promise in designing future drugs. signal molecule synthesized by the Derivatives of these compounds are being enzyme Nitric oxide synthase (NOS). GA Liquorice generated to evaluate their has been found to be an elicitor of nitric Despite a vast range of biological pharmacological purposes for future drug oxide. It functions as a biological response effects like antiinflammatory, antiallergic, use. Glycyrrhizin sulfate has been

364 Natural Product Radiance Review Article synthesized and investigated for anti-HIV discovered in the last millennium and this 10. Hikino H, Recent research on oriental activity in comparison with the parent plant is promising in providing new medicinal plants, In: Economic and medicinal compound glycyrrhizin. Glycyrrhizin molecules, which could be of immense plant research, H Wagner, H Hikino, NR Farnsworth (Eds), London, Academic Press, sulfate was found to have nearly four folds medicinal applications in the present 1985, Vol. 1, 53-85. of the potential antiviral activity in MT-4 millennium. 11. Kamei J, Nakamura R, Ichiki H and Kubo M, cells compared to glycyrrhizin in molar Antitussive principles of Glycyrrhiza radix, 73 terms . Glycyrrhizin derivatives have also References a main component of Kampo preparations been synthesized for the development of Bakumondo-to (Mai-men-dong-tang), E J Pharm, 2003, 69, 159-163. a stable sunscreen compound with a 1. UNESCO Culture and health Orientation 51 potential tyrosinase inhibitory activity . texts- World decade for cultural development 12. Mauricio I, Francischett B, Monterio RQ and Penta-O-cinnamate of glycyrrhizin is the 1988-1997, Document CLT/DEC/PRO- Paris, Guimaraeas JA, Identification of Glycyrrhizin basic structure for the preparation of France 1996, 129. as thrombin inhibitor, Biochim Biophys Res Commun, 1997, 235, 259-263. Niglizin which has a pronounced 2. WHO bulletin, 1985,63, 965-981. antiinflammatory activity combined with 13. Mendes-Silva W, Assafim M, Ruta B, Monteiro antiulcer and hepatoprotective action. 3. Saxena S and Kumar D, Tailoring biodiversity RQ, Guimaraes JA and Zingali RB, for the development of new therapeutics, Nat N-acetylmuramoyl peptide (MDP) is Antithrombotic effect of Glycyrrhizin, a plant- Prod Rad, 2002; 1 (3), 18-25. derived thrombin inhibitor, Thromb Res, glycyrrhizin analog having potential 2003, 112, 93-98. in vitro immunostimulating properties74. 4. UNESCO FIT/504-RAF-48 Terminal Report; promotion of Ethnobotany and sustainable There are ample chances of arriving to 14. Ishii Y and Fuji Y, Effects of FM 100, a use of Plant resources in Africa,1998, 60, fraction of licorice root on serum gastrin pharmacophores with least toxic side Paris. concentration in rats and dogs, Jpn J effects using combinatorial chemistry. The Pharmacol, 1982, 32, 23-27. 5. Shibata S, A drug over the millennia: advances in drug discovery with tools like Pharmacognosy, chemistry and pharmacology 15. Fukai H, Goto K and Tabata, Two Antimicrobial the high throughput systems, proteomics, of licorice, Yakugaku Zasshi, 2000, 120, flavanones from the leaves of Glycyrrhiza genomics and informatics (Bio/Chem. and 849-862. glabra, Chem Pharm Bull, 1988, 36, Pharmaco) have further enhanced the 4174-4176. 6. Dhanaukar SA, Kulkarni RA and Rege NN, evaluation of these newly generated Pharmacology of medicinal plants and natural 16. Hatano T, Shintani Y, Shiota S, Tsuchiya compounds for their future medical products, Indian J Pharm, 2000, 32, T and Yoshida T, Phenolic constituents of applications. 81-118. licorice. VIII. Structures of glicophenone and glicoisoflavanonem and effects of 7. Lauren DR, Jensen DJ, Douglas JA and Follett licorice phenolics on Methicillin–resistant Conclusion JM, Efficient method for determining the Staphylococcus aureus, Chem Glycyrrhizin content of fresh and dried Pharm Bull, 2000, 48, 1286-1292. Phytochemistry has regained its roots, and root extracts, of Glycyrrhiza Species, Phytochem Anal, 2001, 12, 17. Li W, Asada Y and Yoshikawa T, Antimicrobial strength in the drug discovery process in 332–335. from Glycyrrhiza glabra hairy the past few years, as nature is the best root cultures, Planta Med, 1998, 64, inventive chemist providing ample 8. Zhang Guo-qing, Ji Song-gang, Chai Yi-feng, 746-747. Wu Yu-tian and Yin Xue-ping, Determination chemical structural diversity, which could of glycyrrhizin in Radix glycyrrhizae and 18. Hansen LT, Austin JW and Gill TA, Antibacterial be further remodeled using current tools. its preparations by capillary zone effect of protamine in combination with EDTA Glycyrrhiza glabra is one of those electrophoresi, Biomed Chromatogr, and refrigeration, Int J Food Microbiol, ancient plants, which have been used in 1999, 13, 407-409. 2001, 66, 149-161. the traditional pharmacopoeias for its 19. Fukai T, Marumo A, Kaitou K, Kanda T, Terada 9. Ammosov S, Litvinenko VI Triterpenoids of S and Monura T, Anti-Helicobacter pylori multifaceted actions against a variety of Plants of Glycyrrhiza L. and Meristotropis flavonoids from licorice extracts, Life Sci, systemic and non-systemic ailments. The Fisch. Et Mey Genuses (A REVIEW), Pharm 2002, 71, 1449-1463. chemical foundations of these have been Chem J, 2003, 37, 83-94.

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20. Tsukiyama R, Katsura H, Tokuriki N and some RNA and DNA viruses, Indian J subacute hepatic failure, Indian J Med Res, Kobayashi M, Anti-bacterial activity of Pharmacol, 1994, 26, 194-199. 1993, 98, 69-74. Licochalcone A against Spore forming 30. Pliasunova OA, Egoricheva IN, Fediuk NV, 39. Sato H, Goto W, Yamamura J, Kurokawa M, bacteria. Antimicrob Agents, Chemother, Porkrovskii AG, Baltina LA, Murinov I and Kageyama S, Takahara T, Watanabe A and 2002, 46,1226-1230. Tolstikov GA, The anti-HIV activity of beta- Shiraki K, Therapeutic basis of Glycyrrhizin 21. Motsei ML, Lindsey KL, van Staden J and glycyrrhizic acid, Vopr Virsuol, 1992, 37, on chronic hepatitis B, Antiviral Res, 1996, Jager AK, Screening of traditionally used 235-238. 30, 171-177. South African plants for antifungal 31. De Clercq E, Current lead natural products 40. van Rossum TG, Vulto AG, de Man RA, activity against Candida albicans, for the chemotherapy of human Brouwer JT and Schalm SW, Glycyrrhizin as a J Ethanopharmacol, 2003, 86, immunodeficiency virus (HIV) infection, potential treatment of chronic hepatitis C, 235-241. Med Res Rev, 2000, 20, 323-349. Aliment Pharmacol Ther, 1998, 12, 22. Katsura H, Tsukiayama R, Suzuki A and 199-205. 32. Konovalova GG, Tikhaze AK and Lankin VZ, Kobayashi M, In vitro Antimicrobial activity Anti-oxidant activity of parapharmaceutics 41. Jeong HG, You HJ, Park SJ and Moon AR, of bakuchiol against oral microorganisms, containing natural inhibitors of free radical Hepatoprotective effects of 18β -glycyrrhetinic Antimicrob Agents Chemother, 2001, processes, Bull Exp Biol Med, 2000, 130, acids on carbon tetrachloride-induced liver 45, 3009-3013. 658-660. injury, inhibition of cytochrome P450 2E1 23. Haraguchi H, Tanimato K, Tamura Y and expression, Pharmacol Res, 2002, 46, 33. Belinky PA, Aviram M, Mahmood S and Vaya Kinoshita T, Antioxidative and Superoxide 221-227. J, Structural aspects of the inhibitory effects scavenging activities of retrochalcones in on LDL-oxidation, Free Radical Biol Med, 42. Chan HT, Chan C and Ho JW, Inhibition of Glycyrrhiza inflata, Phytochemistry, 1998, 24, 1419-1429. Glycyrrhizic acid on alfatoxin B1-induced 1998, 48, 125-129. cytotoxicity of hepatoma cells, Toxicology, 34. Haraguchi H, Ishikawa H, Mizutani K, Tamura 24. Mitscher LA, Park YH, Clark D and Beal JL, 2003, 188, 211-217. Y and Kinoshita T, Antioxidative and Antimicrobial agents from higher plants, superoxide scavenging activities of 43. Kimura M, Inoue H, Hirabayahi K, Natsume H Antimicrobial isoflavanoids and related retrochalcones in Glycyrrhiza inflata, and Ogihara M, Glycyrrhizin and some substances from Glycyrrhiza glabra L, var Bioorg Med Chem, 1998, 6, 339-346. analogues induce growth of primary cultured typica, J Nat Prod, 1980, 43, 259-262. adult rat hepatocytes via epidermal growth 35. Biondi DM, Rocco C and Ruberto G, New 25. Seedi M, Morteza-Semnani K and Ghoreishi factor receptors, Eur J Pharmacol, 2001, Dihydrostilbene derivatives from the leaves of MR, The treatment of atopic dermatitis with 431, 151-161. Glycycrrhiza glabra and evaluation of licorice gel, J Dermatol Treat, 2003, their anti-oxidant activity, J Nat Prod, 2003, 44. Rafi MM, Vastano BC, Zhu N, Ho CT, Ghai G, 14,153-157. 66, 477-480. Rosen RT, Gallo MA and DiPaola RS, Novel 26. Agarwal R, Wang ZY and Mukhtar H, Inhibition polyphenol molecule isolated from licorice 36. Kuroda M, Mimaki Y, Sashida Y, Mae T, Kishida of mouse skin tumor-initiating activity of root (Glycyrrhiza glabra) induces H, Nishiyama H, Tsukagawa M, Konishi E, DMBA by chronic feeding of Glycyrrhizin in apoptosis, G2/M cell cycle arrest, and Bcl-2 Takahashi K, Kawada T, Nakagawa K and drinking water, Nutr Cancer, 1991, 15, phosphorylation in tumor cell lines, J Agric Kitahara M, Phenolics with PPAR–Ligand - 187-193. Food Chem, 2002, 50, 677-684. binding activity obtained from Licorice 27. Badam L, In vitro antiviral activity of (Glycyrrhiza uralensis roots) and 45. Watanabe M, Hayakawa S, Isemura M, indigenous glycyrrhizin, licorice and ameliorative effects of Glycyrin on genetically Kumazawa S, Nakayama T, Mori C and Glycyrrhizic acid (Sigma) on Japanese diabetic KK-Ay mice, Bioorg Med Chem Kawakami, Identification of licocoumarone Encephalitis Virus, J Commun Dis, 1997, Lett, 2004, Doi 10,1016/jbmcl, 2003.09.052 as an apoptosis –inducing component in 29, 91-99. licorice, Biol Pharm Bull, 2002, 25, 37. Takii H, Kometani T, Nishimura T, NakaeT, 1388-1390. 28. Cinatl J, Morgenstern B, Bauer G, Chandra P, Okada S and Fushiki T, Anti-diabetic effect of Rabenau H and Doerr HW, Glycyrrhizin, an Glycyrrhizin in genetically diabetic KK-Ay mice, 46. Hsiang CY, Lai IL, Chao DC and Ho TY, active component of liquorice roots and Biol Pharm Bull, 2000, 24, 484-487. Differential regulation of activator protein 1 replication of SARS associated coronavirus, activity by glycyrrhizin, Life Sci, 2002, 70, 38. Acharaya SK, Dasarathy S, Tandon A, Joshi YK Lancet, 2003, 361, 2045-2046. 1643-1656. and Tandon BN, Preliminary open trial on 29. Badam L, In vitro studies on the effect of interferon stimulator (SNMC) derived from 47. Nokhodchi H, Nazemiyeh T, Ghafourian D, glycyrrhizin from Glycyrrhizin glabra on Glycyrrhiza glabra in the treatment of Hassan –Zadeh, Valizadeh H and Bahary LAS,

366 Natural Product Radiance Review Article

The effect of glycyrrhizin on the release rate radiation, Phytother Res, 2002, 16, 66. van Rossum TG, de Jong FH, Hop WC, and skin penetration of diclofenac sodium 576-578. Boomsma F and Schalm SW, ‘Pseudo- from topical formulations, Il Framaco, aldosteronism” induced by intravenous 57. Zani F, Cuzzoni MT, Daglia M, Benvenuti S, 2002, 57, 883-888. glycyrrhizin treatment of chronic hepatitis C Vampa G and Mazza P, Inhibition of patients, J Gastroenterol Hepatol, 2001, 48. Asano T, Ishihara K, Morata T, Takeda S and mutagenicity in Salmonella typhimurium 16, 789-795. Aburada M, Permeability of the flavonoids by Glycyrrhiza glabra extract, liquiritigenin and its glycosides in licorice glycyrrhizinic acid, 18-alpha and 18-beta 67. Nussberger J, Investigating mineralocorticoids roots and davidigenin, a hydrogenated glycyrrhetinic acids, Planta Med, 1993, 59, hypertension, J Hypertension, 2003, 2 metabolite of liquiritigenin using human 502-507. (Suppl), 525-530. intestinal cell lines Caco-2, 58. Chen XG and Han R, Effect of Glycyrrhizin on 68. Sigurjonsdottir HA, Franzson L, Manhem K, J Ethnopharmacol, 2003, 89, 285-289. the DNA damage and unscheduled DNA Ragnarsson J, Sigurdsson G and Wallerstedt 49. Yokota T, Nishio H, Kubota T and Muzoguchi synthesis induced by benzo (α) pyrene, Yao S, Licorice induced rise in blood pressure, a M, The inhibitory effect of Glabridin from Xue Xue Bao, 1994, 29, 725-729. linear dose response relationship, J Hum licorice extracts on melanogenesis and Hypertens, 2001, 15(8), 549-552. 59. Liu HM, Sugimoto N, Akiyama T and Maitani inflammation, Pig Cell Res, 1998, 11, T, Constituents and their sweetness of food 69. Elinav E and Chajek- Shaul T, Licorice 355-361. additive enzymatically modified licorice consumption causing severe hypokalemic 50. Nerya O, Vaya J, Musa R, Izarel S, Ben Arie R extract, J Agric Food Chem, 2000, 48, paralysis, Mayo Clin Proc, 2003, 78(6), and Tamir S, Glabrene and isoliquiritigenin 6044-6047. 767-768. as tyrosinase inhibitors from licorice roots, 60. Zhao JF, Kiyohara H, Sun XB, Matsumato T, 70. Yoshida S and Takayama Y, Licorice induced J Agric Food Chem, 2003, 51, Cyong JC, Yamada H, Takemoto N and hyperkalemia as a treatable cause of dropped 1201-1207. Kawamura H, In vitro immunostimulating head syndrome, Clin Neurol Neurosurg, 51. Um SJ, Park MS, Park SH, Han HS, Kwon YJ polysaccharide fractions from the roots of 2003, 105(4), 286-287. and Sin HS, Synthesis of new glycyrrhizinic Glycyrrhiza uralensis, Phytother Res, 71. Paolini M, Pozetti L, Sapone A and Cantelli- acid (GA) derivatives and their effects on 1991, 5, 206-210. Forti G, Effect of Licorice and Glycyrrhizin on tyrosinase activity, Bioorg Med Chem, 61. Matsumoto T, Tanaka M, Yamada H and Cyong murine liver CYP dependent monooxygenases, 2003, 11, 5345-5352. JC, Effect of licorice roots on carrageen- Life Sci, 1998, 62(6),571-582. 52. Ambawade SD, Kasture VS and Kasture SB, induced decrease in immune complexes 72. Eldridge GR, Vervoort HC, Lee CM, Cremin Anticonvulsant activity of roots and rhizomes clearance in mice, J Ethanopharmacol, PA, Williams CT, Hart SM, Goering MG, of Glycyrrhiza glabra, Indian J Pharm, 1996, 63,1-4. Johnson M and Zeng L, High throughput 2002, 34, 251-255. 62. Kroes BH, Beukelman CJ, van der Berg AJ, method for production and analysis of large 53. Tamir S, Eizenberg M, Somjen D, Izrael S and Wolbinlk Gj, van Dijk H and Labadie RP, natural product libraries for drug discovery, Vaya J, Estrogen like activity of glabrene and Inhibition of human complement by beta- Anal Chem, 2002, 74, 3963-3971. glycyrrhetinic acid, Immunology, 1997, other constituents isolated from licorice roots, 73. Nakashima H, Matsui T, Yoshida O and Isowa 90,115-120. J Steroid Biochem Mol Biol, 2000, 78, Y, A new anti-human immunodeficiency virus 291-298. 63. Utsunomiya T, Kobayashi M, Ito M, Herndon substance glycyrrhizin sulfate, endowment of 54. Munday MR, Brush MG and Taylor RW, DN, Pollard RB and Suzuki F, Glycyrrhizin glycyrrhizin with reverse transcriptase Correlations between progesterone, restores the impaired IL-12 production in inhibitory activity by chemical modification, and levels in the premenstrual thermally injured mice, Cytokine, 2001, Jpn J Can Res, 1987, 78,767-771. 14, 49-55. syndrome, Clin Endocrinol, 1981, 14, 74. Blatina LA, Chemical modification of 1-9. 64. Jeong HG and Kim JY, Induction of inducible Glycyrrhizic acid as a route to bioactive nitric oxide synthase expression by 18β- compounds for medicine, Curr Med 55. Ofir R, Tamir S, Khatib S and Vaya J, Inhibition glycyrrhetinic acids in macrophages, FEBS Chem, 2003, 10, 155-171. of serotinin re-uptake by licorice constituents, Letters, 2002, 513, 208-212. J Mol Neurosci, 2003, 20, 135-140. 65. Kanda H, Sakurai M, and Arima K, Licorice of 56. Shetty TK, Satav JG and Nair CK, Protection of “Shukuyaku Kanzou tou” induced DNA and microsomal membranes in vitro by pseudoaldosteronism, Hinyokika Kiyo, Glycyrrhiza glabra L, against gamma 2004, 50, 215-217.

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