The Pharmacological Activities of Glycyrrhizinic Acid (“Glycyrrhizin”) and Glycyrrhetinic Acid

  • Cedric Stephan Graebin
Living reference work entry
Part of the Reference Series in Phytochemistry book series (RSP)


Glycyrrhizin or, more correctly, Glycyrrhizinic acid is a triterpenoid saponin obtained from the root and rhizome extracts of Licorice (Glycyrrhiza glabra), being commonly used as a sweetener, being reported as – at least – 30 times sweeter than sucrose. This natural product, along with its aglycone glycyrrhetinic acid, is known in the literature for its several pharmacological and biological activities. This chapter summarizes the activities reported in the literature for the saponin and its aglycone since 2010.


Glycyrrhizinic acid Glycyrrhizin Glycyrrhetinic acid Glycyrrhiza glabra Liquorice 



This work is partly supported by grants from the Brazilian Government Science and Research Council (in Portuguese: Conselho Nacional de Pesquisa or CNPq) and the Rio de Janeiro State Research Foundation (Fundação de Apoio à Pesquisa do Estado do Rio de Janeiro or FAPERJ).


  1. 1.
    World Health Organization (2006) Safety evaluation of certain food additives. WHO Press, GenevaGoogle Scholar
  2. 2.
    European Comission Scientific Comiteee on Food (2003) Opinion of the scientific committee on food on glycyrrhizinic acid and its ammonium salt. European Commission. Accessed 29 Jan 2016
  3. 3.
    Graebin CS, Verli H, Guimarães JA (2010) Glycyrrhizin and glycyrrhetic acid: scaffolds to promising new pharmacologically active compounds. J Braz Chem Soc 21:1595–1615CrossRefGoogle Scholar
  4. 4.
    Ijeda K, Arase Y, Kobayashi M, Saitoh S, Someya T, Hosaka T, Sekazi H, Akuta N, Suzuki S, Suzuki F, Kumada H (2006) A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients. Dig Dis Sci 51:603–609CrossRefGoogle Scholar
  5. 5.
    Glavac KN, Kreft S (2012) Excretion profile of glycyrrhizin metabolite in human urine. Food Chem 131:305–308CrossRefGoogle Scholar
  6. 6.
    Baltina LA (2003) Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr Med Chem 10:155–171CrossRefGoogle Scholar
  7. 7.
    Ming LJ, Yin ACY (2013) Therapeutic effects of glycyrrhizic acid. Nat Prod Comm 8:415–418Google Scholar
  8. 8.
    American Chemical Society (2016) SciFinder. Accessed 29 Jan 2016.
  9. 9.
    Wang H, Chu Z, Gao Y, Huang M (2015) Effect of glycyrrhizin on gastric cancer BGC-823 cell proliferation. Shijie Huaren Xiaohua Zazhi 23:2868–2873Google Scholar
  10. 10.
    Yang YA, Tang WJ, Zhang X, Yuan JW, Liu XH, Zhu HL (2014) Synthesis, molecular docking and biological evaluation of glycyrrhizin analogs as anticancer agents targeting EGFR. Molecules 19:6368–6381CrossRefGoogle Scholar
  11. 11.
    Huang RY, Chu YL, Jiang ZB, Chen XM, Zhang X, Zeng X (2014) Glycyrrhizin suppresses lung adenocarcinoma cell growth through inhibition of thromboxane synthase. Cell Phys Biochem 33:375–388CrossRefGoogle Scholar
  12. 12.
    Smolarczyk R, Cichon T, Matuszczak S, Mitrus I, Lesiak M, Kobusinska M, Kamysz W, Jarosz M, Sieron A, Szala S (2012) The role of glycyrrhizin, an inhibitor of HMGB1 protein, in anticancer therapy. Arch Immun Therap Exper 60:391–399CrossRefGoogle Scholar
  13. 13.
    Wang W, Chen X, Zhang J, Zhao Y, Li S, Tan L, Gao J, Fang X, Luo A (2015) Glycyrrhizin attenuates isoflurane-induced cognitive deficits in neonatal rats via its anti-inflammatory activity. Neuroscience 316:328–336CrossRefGoogle Scholar
  14. 14.
    Zhang J, Wu Y, Weng Z, Zhou T, Feng T, Lin Y (2014) Glycyrrhizin protects brain against ischemia-reperfusion injury in mice through HMGB1-TLR4-IL-17A signaling pathway. Brain Res 1582:176–186CrossRefGoogle Scholar
  15. 15.
    Liu Z, Zhong J, Gao E, Yang H (2014) Effects of glycyrrhizin acid and licorice flavonoids on LPS-induced cytokines expression in macrophage. Zhongguo Zhongyao Zazhi 39:3841–3845Google Scholar
  16. 16.
    Fu Y, Zhou E, Wei Z, Song X, Liu Z, Wang T, Wang W, Zhang N, Liu G, Yang Z (2014) Glycyrrhizin inhibits lipopolysaccharide-induced inflammatory response by reducing TLR4 recruitment into lipid rafts in RAW264.7 cells. Biochimica Biophys Acta Gen Subjects 1840:1755–1764CrossRefGoogle Scholar
  17. 17.
    Wang HL, Li YX, Niu YT, Zheng J, Wu J, Shi GJ, Ma L, Niu Y, Sun T, Yu JQ (2015) Observing anti-inflammatory and anti-nociceptive activities of glycyrrhizin through regulating COX-2 and pro-inflammatory cytokines expressions in mice. Inflammation 38:2269–2278CrossRefGoogle Scholar
  18. 18.
    Chang CZ, Wu SC, Kwan AL (2015) Glycyrrhizin attenuates proinflammatory cytokines through a peroxisome proliferator-activated receptor-γ-dependent mechanism and experimental vasospasm in a rat model. J Vasc Res 52:12–21CrossRefGoogle Scholar
  19. 19.
    Chang CZ, Wu SC, Kwan AL (2014) Glycyrrhizin attenuates toll like receptor-2, -4 and experimental vasospasm in a rat model. J Immun Res 740549:1–9CrossRefGoogle Scholar
  20. 20.
    Xiao J, Liu J, Zhang Q (2014) Influence of compound glycyrrhizin on the functions of Treg and TH17 cells in children with henochschonlein purpura. Qingdao Daxue Yixueyuan Xuebao 50:315–317Google Scholar
  21. 21.
    Zhou J, Ma N, Qie Y, Shen J (2014) Efficiency of compound glycyrrhizin in treatment of 42 cases with chronic urticaria. Zhongguo Yaoye 23:117Google Scholar
  22. 22.
    Luo X, Li X, Yang L, Wang X (2014) Efficacy of magnesium isoglycyrrhizinate in treatment of hepatitis E with severe jaundice. Linchuang Gandanbing Zazhi 30:537–539Google Scholar
  23. 23.
    Zhang XX, Wu J, Xu Y, Zou X, Hu SY (2014) Clinical observation of compound glycyrrhizin for the prevention of liver and hematological system toxicity after chemotherapy for digestive tract cancer. Zhongguo Yaofang 25:4364–4366Google Scholar
  24. 24.
    Hsiang CY, Lin LJ, Kao ST, Lo HY, Chou ST, Ho TY (2015) Glycyrrhizin, silymarin, and ursodeoxycholic acid regulate a common hepatoprotective pathway in HepG2 cells. Phytomedicine 22:768–777CrossRefGoogle Scholar
  25. 25.
    Meng W, Yu LZ, Wang L (2013) Effects of compound glycyrrhizin on liver function in patients with alcoholic liver disease: a meta-analysis. Zhongguo Yaofang 24:1116–1118Google Scholar
  26. 26.
    Yin J, Feng H, Chen S, Yang L (2013) Effects of compound glycyrrhizin preparation on IL-17 and ANA in patients with chronic hepatitis B. Jiangsu Yiyao 39:1280–1281Google Scholar
  27. 27.
    Cai L, Wu Y, Zhang J (2012) Comparison of the efficacy of two glycyrrhizin in treatment of chronic hepatitis B. Yaowu Liuxingbingxue Zazhi 21:160–161Google Scholar
  28. 28.
    Ding TP, Qu Y, Lu LG, Shi GL, Wang RF (2012) 18α-Glycyrrhizin ameliorates oxidative stress in rats with CCl4-induced liver fibrosis. Shijie Huaren Xiaohua Zazhi 20:1819–1823Google Scholar
  29. 29.
    Smith G, Stubbins MJ, Harries LW, Wolf CR (1999) Molecular genetics of the human cytochrome P450 monooxygenase superfamily. Xenobiotica 28:1129–1165CrossRefGoogle Scholar
  30. 30.
    Wang YG, Zhou JM, Ma ZC, Li H, Liang QD, Tan HL, Xiao CR, Zhang BL, Gao Y (2012) Pregnane X receptor mediated-transcription regulation of CYP3A by glycyrrhizin: a possible mechanism for its hepatoprotective property against lithocholic acid-induced injury. Chemico-Biol Interact 200:11–20CrossRefGoogle Scholar
  31. 31.
    Chen Y, Wan X, Sun J, Wang W, Zhang S (2012) Hepato-protective activity of glycyrrhizin, liquiritin and isoliquiritigenin on HL-7702 cells injury induced by acetaminophen. Zhongguo Shiyan Fangjixue Zazhi 18:245–248Google Scholar
  32. 32.
    Gwak GY, Moon TG, Lee DH, Yoo BC (2012) Glycyrrhizin attenuates HMGB1-induced hepatocyte apoptosis by inhibiting the p38-dependent mitochondrial pathway. World J Gastr 18:679–684CrossRefGoogle Scholar
  33. 33.
    Duan E, Wang D, Fang L, Ma J, Luo J, Chen H, Li K, Xiao S (2015) Suppression of porcine reproductive and respiratory syndrome virus proliferation by glycyrrhizin. Antivir Res 120:122–125CrossRefGoogle Scholar
  34. 34.
    Li Z, Zhao Y, Lin W, Ye M, Ling X (2015) Rapid screening and identification of active ingredients in licorice extract interacting with V3 loop region of HIV-1 gp120 using ACE and CE-MS. J Pharm Biom Anal 111:28–35CrossRefGoogle Scholar
  35. 35.
    Matsumoto Y, Matsuura T, Aoyagi H, Matsuda M, Hmwe SS, Date T, Watanabe N, Watashi K, Suzuki R, Ichinose S, Wake K, Suzuki T, Miyamura T, Wakita T, Aizaki H (2013) Antiviral activity of glycyrrhizin against hepatitis C virus in vitro. PLoS One 8:e68992CrossRefGoogle Scholar
  36. 36.
    Ashfaq UA, Nawaz Z, Riazuddin S (2011) Glycyrrhizin as antiviral agent against Hepatitis C virus. J Trans Med 9:112CrossRefGoogle Scholar
  37. 37.
    Xiao Q (2014) Zhou X (2014) Glycyrrhizin inhibits human neutrophil elastase-induced mucin 5 AC overproduction in human bronchial epithelial cells. Zhongnan Daxue Xuebao, Yixueban 39:252–257Google Scholar
  38. 38.
    Sil R, Sen S, Chakraborti AS (2015) Interaction of glycyrrhizin with human haemoglobin. Curr Sci 108:364–371Google Scholar
  39. 39.
    Francischetti IMB, Monteiro RQ, Guimarães JA (1997) Identification of glycyrrhizin as a thrombin inhibitor. Biochem Biophys Res Comm 9:259–263Google Scholar
  40. 40.
    Mendes-Silva W, Assafim M, Ruta B, Monteiro RQ, Guimarães JA, Zingali RB (2003) Antithrombotic effect of glycyrrhizin, a plant-derived thrombin inhibitor. Thromb Res 112:93–98CrossRefGoogle Scholar
  41. 41.
    Paula FT, Frauches PQ, Pedebos C, Berger M, Gnoatto SC, Gossmann G, Verli H, Guimarães JA, Graebin CS (2013) Improving the thrombin inhibitory activity of glycyrrhizin, a triterpenic saponin, through a molecular simplification of the carbohydrate moiety. Chem Biol Drug Design 82:756–760CrossRefGoogle Scholar
  42. 42.
    Imai K, Takagi Y, Iwazaki A, Nakanishi K (2014) Radical scavenging ability of glycyrrhizin. Free Rad Antioxid 3:40–42CrossRefGoogle Scholar
  43. 43.
    Csuk R (2014) Recent developments in the synthesis of antitumor-active glycyrrhetinic acid derivatives. Mini-Rev Org Chem 11:253–261CrossRefGoogle Scholar
  44. 44.
    Kim H, Kim SY, Lee JH, Han Y (2011) Antitumor effect of 18β-glycyrrhetinic acid against human tumor xenografts caused by A549 cancer cell. Yakhak Hoechi 55:39–44Google Scholar
  45. 45.
    Yamaguchi H, Yu T, Kidachi Y, Akitaya T, Yoshida K, Kamiie K, Noshita T, Umetsu H, Ryoyama K (2011) Selective toxicity of glycyrrhetinic acid against tumorigenic r/m HM-SFME-1 cells is potentially attributed to downregulation of glutathione. Biochimie 93:1172–1178CrossRefGoogle Scholar
  46. 46.
    Xu S, Zhou L, Liu Z, Chen B, Li Y (2011) Glycyrrhetinic acid induces apoptosis and alters survivin gene expression in human myeloma cell line U266. Zhongguo Shiyan Xueyexue Zazhi 19:652–655Google Scholar
  47. 47.
    Kowsalya R, Vishwanathan P, Manoharan S (2011) Chemopreventive potential of 18β-glycyrrhetinic acid: an active constituent of liquorice, in 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. Pakistan J Biol Sci 14:619–626CrossRefGoogle Scholar
  48. 48.
    Sharma G, Kar S, Palit S, Das PK (2012) 18β-glycyrrhetinic acid (concur) induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF-7 cells. J Cell Phys 227:1923–1931CrossRefGoogle Scholar
  49. 49.
    Kuang P, Zhao W, Su W, Zhang Z, Zhang L, Liu J, Ren G, Yin Z, Wang X (2013) 18β-glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell-mediated immunosuppression in mice. Int J Cancer 132:1831–1841CrossRefGoogle Scholar
  50. 50.
    Xie F, Cao Y, Liu GR, Yang XH, Dai Q, Chen W (2013) Mechanism underlying the inhibitory effect of glycyrrhetinic acid on epidermal growth factor-induced proliferation of HaCaT cells. Zhonghua Pifuke Zazhi 46:278–281Google Scholar
  51. 51.
    Li ZL, Sun D, Yang YC, Xu XL, Kong CZ (2012) 18β-glycyrrhetinic acid inhibits human 17β-hydroxysteroid dehydrogenase type III and induces cell apoptosis via activation of eIF2α in prostate cancer. Zhongguo Yike Daxue Xuebao 41:882–885Google Scholar
  52. 52.
    Wang D, Wong HK, Feng YB, Zhang ZJ (2014) 18beta-Glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neuro-Oncology 116:221–230CrossRefGoogle Scholar
  53. 53.
    Huang RY, Chu YL, Huang QC, Chen XM, Jiang ZB, Zhang X, Zeng X (2014) 18β-Glycyrrhetinic acid suppresses cell proliferation through inhibiting thromboxane synthase in non-small cell lung cancer. PLoS One 9:e93690CrossRefGoogle Scholar
  54. 54.
    Jayasooriya RGPT, Dilshara MG, Park SR, Choi YH, Hyun JW, Chang WY, Kim GY (2014) 18β-Glycyrrhetinic acid suppresses TNF-α induced matrix metalloproteinase-9 and vascular endothelial growth factor by suppressing the Akt-dependent NF-κB pathway. Toxicol In Vitro 28:751–758CrossRefGoogle Scholar
  55. 55.
    Mahmoud AM, Al Dera HS (2015) 18β-glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARγ and Nrf2 upregulation. Genes Nutr 10:1–13CrossRefGoogle Scholar
  56. 56.
    Chen S, Zou L, Li L, Wu T (2013) The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. PLoS One 8:e53662CrossRefGoogle Scholar
  57. 57.
    Hasan SK, Khan R, Ali N, Khan AQ, Rehman MU, Tahir M, Lateef A, Nafees S, Mehdi SJ, Rashid S, Shalid A, Sultana S (2015) 18-β glycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in Wistar rats: role in hyperproliferation, inflammation and oxidative stress. Human Exp Toxicol 34:628–641CrossRefGoogle Scholar
  58. 58.
    Gupta P, Das PK, Ukil A (2015) Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by toll-like receptor-dependent canonical and noncanonical p38 activation. Antimicrob Ag Chemother 59:2531–2539CrossRefGoogle Scholar
  59. 59.
    Ukil A, Kar S, Srivastav S, Ghosh K, Das PK (2011) Curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular MAP kinases. PLoS One 6:e29062CrossRefGoogle Scholar
  60. 60.
    Kalani K, Agarwal J, Alam S, Khan F, Pal A, Srivastava SK (2013) In silico and in vivo anti-malarial studies of 18β glycyrrhetinic acid from Glycyrrhiza glabra. PLoS One 8:e74761CrossRefGoogle Scholar
  61. 61.
    Kalani K, Kushwaha V, Verma R, Murthy PK, Srivastava SK (2013) Glycyrrhetinic acid and its analogs: a new class of antifilarial agents. Bioorg Med Chem Lett 23:2566–2570CrossRefGoogle Scholar
  62. 62.
    Long DR, Mead J, Hendricks JM, Hardy ME, Voyich JM (2013) 18β-glycyrrhetinic acid inhibits methicillin-resistant Staphylococcus aureus survival and attenuates virulence gene expression. Antimicrob Ag Chemother 57:241–247CrossRefGoogle Scholar
  63. 63.
    Kim SR, Jeon HJ, Park HJ, Kim MK, Choi WS, Jang HO, Bae SK, Jeong CH, Bae MK (2013) Glycyrrhetinic acid inhibits Porphyromonas gingivalis lipopolysaccharide-induced vascular permeability via the suppression of interleukin-8. Inflammation Res 62:145–154CrossRefGoogle Scholar
  64. 64.
    Puchner A, Hayer S, Niederreiter B, Hladik A, Blueml S, Bonelli M, Scheinecker C, Smolen J, Redlich K (2012) Effects of 18β-glycyrrhetinic acid in hTNFtg mice – a model of rheumatoid arthritis. Wiener Klinische Wochenschrift 124:170–176CrossRefGoogle Scholar
  65. 65.
    Chen HJ, Kang SP, Lee IJ, Lin YL (2014) Glycyrrhetinic acid suppressed NF-κB activation in TNF-α-induced hepatocytes. J Agric Food Chem 62:618–625CrossRefGoogle Scholar
  66. 66.
    Wang CY, Kao TC, Lo WH, Yen GC (2011) Glycyrrhizic acid and 18β-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-κB through PI3K p110δ and p110γ inhibitions. J Agric Food Chem 59:7726–7733CrossRefGoogle Scholar
  67. 67.
    Kao TC, Shyu MH, Yen GC (2010) Glycyrrhizic acid and 18β-glycyrrhetinic acid inhibit inflammation via PI3K/Akt/GSK3β signaling and glucocorticoid receptor activation. J Agric Food Chem 58:8623–8629CrossRefGoogle Scholar
  68. 68.
    Zhang H, Huang Q, Zhai J, Zhao Y, Zhang L, Chen Y, Zhang R, Li Q, Hu X (2015) Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor. Acta Pharmacol Sinica 36:1145–1150CrossRefGoogle Scholar
  69. 69.
    Wu CH, Chen AZ, Yen GC (2015) Protective effects of glycyrrhizic acid and 18β-glycyrrhetinic acid against cisplatin-induced nephrotoxicity in BALB/c mice. J Agric Food Chem 63:1200–1209CrossRefGoogle Scholar
  70. 70.
    Kong SZ, Chen HM, Yu XT, Zhang X, Feng XX, Kang XH, Li WJ, Huang N, Luo H, Su ZR (2015) The protective effect of 18β-glycyrrhetinic acid against UV irradiation induced photoaging in mice. Exp Geront 61:147–155CrossRefGoogle Scholar
  71. 71.
    Moon MH, Jeong JK, Lee YJ, Seol JW, Ahn DC, Kim IS, Park SY (2012) 18β-glycyrrhetinic acid inhibits adipogenic differentiation and stimulates lipolysis. Biochem Biophys Res Comm 420:805–810CrossRefGoogle Scholar
  72. 72.
    Park M, Lee JH, Choi JK, Hong YD, Bae IH, Lim KM, Park YH, Ha H (2014) 18β-glycyrrhetinic acid attenuates anandamide-induced adiposity and high-fat diet induced obesity. Mol Nutr Food Res 58:1436–1446CrossRefGoogle Scholar
  73. 73.
    Jiang L, Wang Q, Shen S, Xiao T, Li Y (2014) Discovery of glycyrrhetinic acid as an orally active, direct inhibitor of blood coagulation factor Xa. Thromb Res 133:501–506CrossRefGoogle Scholar
  74. 74.
    Hardy ME, Hendricks JM, Paulson JM, Faunce NR (2012) 18β-glycyrrhetinic acid inhibits rotavirus replication in culture. Virology J 9:96CrossRefGoogle Scholar
  75. 75.
    Food and Drug Administration (2015) CFR – code of federal regulations title 21. US Food and Drug Administration. Accessed 29 Jan 2016
  76. 76.
    Dougall IG, Unitt J (2015) Evaluation of the biological activity of compounds: techniques and mechanism of action studies. In: Wermuth CG, Aldous D, Raboisson P, Rognan D (eds) The practice of medicinal chemistry, 4th edn. Elsevier, LondonGoogle Scholar

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© Springer International Publishing AG 2016

Authors and Affiliations

  1. 1.Chemistry DepartmentFederal Rural University of Rio de JaneiroSeropédicaBrazil

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