Liquorice, a unique "guide drug" of traditional Chinese medicine: a review of its role in drug interactions.

ETHNOPHARMACOLOGICAL RELEVANCE Liquorice is the root of Glycyrrhiza uralensis Fisch. or Glycyrrhiza glabra L., Leguminosae. It is a widely used herbal medicine native to southern Europe and parts of Asia and has beneficial applications in both the medicinal and the confectionery sectors. Unlike its usage in Europe, liquorice in traditional Chinese medicine is commonly combined with other herbs in a single prescription, as a unique "guide drug" to enhance the effectiveness of other ingredients, to reduce toxicity, and to improve flavor in almost half of Chinese herbal formulas. A review on phytochemical and pharmacological research to explain this unique "guide" effect is suggested for future investigations. MATERIALS AND METHODS The information was collected from scientific journals, books, and pharmacopeia. The studies about the traditional uses, randomized controlled trials, chemical, pharmacological and pharmacokinetic data related to liquorice-herb/drug interaction or combination were included in the review. RESULTS According to recent reports, the "guide" effect of liquorice is partially through components transformed in liquorice-drug interaction; altering enzyme activity of P450 isoforms, as evidenced by induction of model probe substrates; and modulation of drug transporter proteins such as intestinal P-glycoprotein. CONCLUSION The overview and comparison of traditional uses of liquorice with recent pharmacological studies and randomized controlled trials provide new insights into this ancient drug for future investigations and clinical use, especially in drug combination.

[1]  P. Hollenberg,et al.  The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[2]  Y. Kim,et al.  18beta-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. , 2008, Life sciences.

[3]  X. Shen,et al.  [Effects of glycyrrhizin on genes expression during the process of liver fibrosis]. , 2003, Zhonghua yi xue za zhi.

[4]  Liu Xiao The Increasing Effect and Reducing Ill Effect Principe of Compatibility of Radix Aconiti Laterlis Preparata and Radix Glycyrrhizae , 2003 .

[5]  Shiuan-Pey Lin,et al.  Liquorice reduced cyclosporine bioavailability by activating P-glycoprotein and CYP 3A. , 2012, Food chemistry.

[6]  Sai-jun Li,et al.  [Study on the interactions between rhizoma coptidis and radix glycyrrhiza]. , 2007, Guang pu xue yu guang pu fen xi = Guang pu.

[7]  Chaoming Mao,et al.  18β-Glycyrrhetinic Acid Ameliorates Acute Propionibacterium acnes-induced Liver Injury through Inhibition of Macrophage Inflammatory Protein-1α* , 2009, The Journal of Biological Chemistry.

[8]  Yunqing Cai,et al.  Liquiritigenin Inhibits Tumor Growth and Vascularization in a Mouse Model of Hela Cells , 2012, Molecules.

[9]  Yuguang Wang,et al.  [Effects of 18beta-glycyrrhizic acid and 18alpha-glycyrrhizic acid on mRNA and protein expression of cytochrome P450 3A in cultured rat primary hepatocyte]. , 2009, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[10]  K. Kölble Regional mapping of short tandem repeats on human chromosome 10: cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225. , 1993, Genomics.

[11]  M. Eisenhut,et al.  A history of the therapeutic use of liquorice in Europe , 2005, Journal of Ethnopharmacology.

[12]  H. Fujii,et al.  Glycyrrhizin Prevents Liver Injury by Inhibition of High-Mobility Group Box 1 Production by Kupffer Cells after Ischemia-Reperfusion in Rats , 2011, Journal of Pharmacology and Experimental Therapeutics.

[13]  Gang Bai,et al.  Protective effects of glycyrrhizin against β₂-adrenergic receptor agonist-induced receptor internalization and cell apoptosis. , 2011, Biological & pharmaceutical bulletin.

[14]  Surveillance of suspected adverse reactions to herbal products used as laxatives , 2012, European Journal of Clinical Pharmacology.

[15]  Jiqiang Guo,et al.  Protective effect of glycyrrhizin, glycyrrhetic acid and matrine on acute cholestasis induced by alpha-naphthyl isothiocyanate in rats. , 2007, Planta medica.

[16]  G. Sigurdsson,et al.  Liquorice-induced rise in blood pressure: a linear dose-response relationship , 2001, Journal of Human Hypertension.

[17]  C. China Pharmacopoeia,et al.  Pharmacopoeia of the People's Republic of China , 2010 .

[18]  Tao Jiang,et al.  Glycyrrhizin treatment is associated with attenuation of lipopolysaccharide-induced acute lung injury by inhibiting cyclooxygenase-2 and inducible nitric oxide synthase expression. , 2011, The Journal of surgical research.

[19]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[20]  A. Fugh-Berman Herbal medicinals: selected clinical considerations, focusing on known or potential drug-herb interactions. , 1999, Archives of internal medicine.

[21]  G. Burdock,et al.  Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. , 2006, Regulatory toxicology and pharmacology : RTP.

[22]  S. Tsui,et al.  Analysis of proprietary Chinese medicines for the presence of toxic ingredients by LC/MS/MS. , 2002, Journal of pharmaceutical and biomedical analysis.

[23]  P. Mukherjee,et al.  Exploring the Possible Metabolism Mediated Interaction of Glycyrrhiza glabra Extract with CYP3A4 and CYP2D6 , 2011, Phytotherapy research : PTR.

[24]  Yunqing Cai,et al.  Inhibitory Effect of Liquiritigenin on Migration Via Downregulation ProMMP-2 and PI3K/Akt Signaling Pathway in Human Lung Adenocarcinoma A549 cells , 2012, Nutrition and cancer.

[25]  Guo Peng Cytoprotective effect and its mechanisms of isoliquiritigenin on acetaminophen induced acute injury of hepatocytes , 2008 .

[26]  P. Han,et al.  Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion , 2012, Neurobiology of Disease.

[27]  A. Ziaee,et al.  The Efficacy of Licorice Root Extract in Decreasing Transaminase Activities in Non‐alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial , 2012, Phytotherapy research : PTR.

[28]  B. Kang,et al.  Licochalcone E activates Nrf2/antioxidant response element signaling pathway in both neuronal and microglial cells: therapeutic relevance to neurodegenerative disease. , 2012, The Journal of nutritional biochemistry.

[29]  You-jin Lee,et al.  18β-Glycyrrhetinic acid inhibits adipogenic differentiation and stimulates lipolysis. , 2012, Biochemical and biophysical research communications.

[30]  G. Cantelli-forti,et al.  Effect of liquorice and glycyrrhizin on rat liver carcinogen metabolizing enzymes. , 1999, Cancer letters.

[31]  Neeraj Kumar,et al.  Evaluation of antigenotoxic activity of isoliquiritin apioside from Glycyrrhiza glabra L. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[32]  I. Kitagawa Licorice root. A natural sweetener and an important ingredient in Chinese medicine , 2002 .

[33]  Konrad Köble Regional mapping of short tandem repeats on humanchromosome 10: Cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225 , 1993 .

[34]  Xiaodong Sun,et al.  Glycyrrhizin could reduce ocular hypertension induced by triamcinolone acetonide in rabbits , 2011, Molecular vision.

[35]  D. Touw,et al.  Clinical implications of genetic polymorphisms and drug interactions mediated by cytochrome P-450 enzymes. , 1997, Drug metabolism and drug interactions.

[36]  Li Liu,et al.  In vitro metabolism of glycyrrhetic acid by human cytochrome P450. , 2011, Yao xue xue bao = Acta pharmaceutica Sinica.

[37]  A. Li,et al.  Substrates of human hepatic cytochrome P450 3A4. , 1995, Toxicology.

[38]  A. Moghadamnia,et al.  The efficacy of the bioadhesive patches containing licorice extract in the management of recurrent aphthous stomatitis , 2009, Phytotherapy research : PTR.

[39]  J. Park,et al.  Antiangiogenic effect of licochalcone A. , 2010, Biochemical pharmacology.

[40]  T. Mashino,et al.  Licochalcone A Potently Inhibits Tumor Necrosis Factor α-Induced Nuclear Factor-κB Activation through the Direct Inhibition of IκB Kinase Complex Activation , 2009, Molecular Pharmacology.

[41]  Min Ye,et al.  Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice). , 2009, Journal of chromatography. A.

[42]  Hai-Yan Quan,et al.  Licochalcone A prevents adipocyte differentiation and lipogenesis via suppression of peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein pathways. , 2012, Journal of agricultural and food chemistry.

[43]  G. Cantelli-forti,et al.  Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. , 1998, Life sciences.

[44]  Yeong Shik Kim,et al.  In vitro and in vivo antiallergic effects of Glycyrrhiza glabra and its components. , 2007, Planta medica.

[45]  A. Davey,et al.  Effects of glycyrrhizin on biliary transport and hepatic levels of glutathione in rats , 2012, Biopharmaceutics & drug disposition.

[46]  Kiyomi Ito,et al.  Effects of Kampo medicines on P-glycoprotein. , 2009, Biological & pharmaceutical bulletin.

[47]  Dan Yang,et al.  Pharmacopoeia of the People's Republic of China (2010 Edition): A Milestone in Development of China's Healthcare , 2010 .

[48]  J. Alexander,et al.  Glycyrrhizic acid in liquorice--evaluation of health hazard. , 1993, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[49]  Xuming Deng,et al.  Antimicrobial activity of licochalcone E against Staphylococcus aureus and its impact on the production of staphylococcal alpha-toxin. , 2012, Journal of microbiology and biotechnology.

[50]  J. Ruan,et al.  [Studies on liver-toxicity in rhigoma of Dioscorea bulbifera]. , 2003, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[51]  W. Sheu,et al.  Combined extractives of red yeast rice, bitter gourd, chlorella, soy protein, and licorice improve total cholesterol, low-density lipoprotein cholesterol, and triglyceride in subjects with metabolic syndrome. , 2012, Nutrition research.

[52]  M. Bernardi,et al.  Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. , 1994, Life sciences.

[53]  Ya-bin Sun,et al.  [Effect of Glycyrrhiza inflata and Daphne genkwa on permeabilities of rhodamine 123, a P-glycoprotein substrate across rat jejunum membranes in vitro]. , 2008, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[54]  Wenxiu Zhao,et al.  18β‐glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell‐mediated immunosuppression in mice , 2013, International journal of cancer.

[55]  Ji-Yeon Kim,et al.  Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. , 2008, European journal of pharmacology.

[56]  A. Chakraborti,et al.  Ameliorative effects of glycyrrhizin on streptozotocin‐induced diabetes in rats , 2011, The Journal of pharmacy and pharmacology.

[57]  S. Tsukamoto,et al.  CYP3A4 inhibitors isolated from Licorice. , 2005, Biological & pharmaceutical bulletin.

[58]  Paul C. H. Li,et al.  Chemical analysis of raw, dry‐roasted, and honey‐roasted licorice by capillary electrophoresis , 2004, Electrophoresis.

[59]  Feng Chen,et al.  Absorption, disposition, and pharmacokinetics of saponins from Chinese medicinal herbs: what do we know and what do we need to know more? , 2012, Current drug metabolism.

[60]  Ying Sun,et al.  [Magnesium isoglycyrrhizinate in the treatment of chronic liver diseases: a randomized, double-blind, multi-doses, active drug controlled, multi-center study]. , 2009, Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology.

[61]  Jeffrey P. Jones,et al.  Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. , 2005, Annual review of pharmacology and toxicology.

[62]  Cheol‐Hee Kim,et al.  In vitro and in vivo osteogenic activity of licochalcone A , 2012, Amino Acids.

[63]  Wei Jiang,et al.  Glycyrrhizin regulates CD4+T cell response during liver fibrogenesis via JNK, ERK and PI3K/AKT pathway. , 2012, International immunopharmacology.

[64]  Xia Li,et al.  Safety and tolerability of an antiasthma herbal Formula (ASHMI) in adult subjects with asthma: a randomized, double-blinded, placebo-controlled, dose-escalation phase I study. , 2009, Journal of alternative and complementary medicine.

[65]  Min Huang,et al.  Interactions of Herbs with Cytochrome P450 , 2003, Drug metabolism reviews.

[66]  P. Hrelia,et al.  Interaction of licorice on glycyrrhizin pharmacokinetics. , 1994, Environmental health perspectives.

[67]  P. Das,et al.  18β‐glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF‐7 cells , 2012, Journal of cellular physiology.

[68]  Jayachandra,et al.  An Extract of Glycyrrhiza glabra (GutGard) Alleviates Symptoms of Functional Dyspepsia: A Randomized, Double-Blind, Placebo-Controlled Study , 2011, Evidence-based complementary and alternative medicine : eCAM.

[69]  Sangita B. Patil,et al.  Glycyrrhiza uralensis Flavonoids Present in Anti‐Asthma Formula, ASHMITM, Inhibit Memory Th2 Responses in Vitro and in Vivo , 2013, Phytotherapy research : PTR.

[70]  A. Villari,et al.  Toxicological assessment of liquorice: biliary excretion in rats. , 1997, Pharmacological research.

[71]  J. Park,et al.  Antitumor and antimetastatic effects of licochalcone A in mouse models , 2010, Journal of Molecular Medicine.

[72]  Yun Cai,et al.  Liquiritigenin Inhibits Serum‐induced HIF‐1α and VEGF Expression via the AKT/mTOR‐p70S6K Signalling Pathway in HeLa Cells , 2012, Phytotherapy research : PTR.

[73]  M. Houssen,et al.  Natural anti-inflammatory products and leukotriene inhibitors as complementary therapy for bronchial asthma. , 2010, Clinical biochemistry.

[74]  J. Park,et al.  Induction of apoptosis by the licochalcone E in endothelial cells via modulation of NF-kappaB and Bcl-2 Family. , 2007, Biological & pharmaceutical bulletin.

[75]  T. Moritani,et al.  Effect of the combination of ginseng, oriental bezoar and glycyrrhiza on autonomic nervous activity and immune system under mental arithmetic stress. , 2008, Journal of nutritional science and vitaminology.

[76]  Hong Gyu Park,et al.  Licochalcone E has an antidiabetic effect. , 2012, The Journal of nutritional biochemistry.

[77]  P. Liu,et al.  Antidepressant-like effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[78]  M. Karimi,et al.  The effect of glycyrrhizin on maturation and T cell stimulating activity of dendritic cells. , 2012, Cellular immunology.