Journal of Ethnopharmacology 150 (2013) 781–790 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep Review Liquorice, a unique “guide drug” of traditional Chinese medicine: A review of its role in drug interactions Xiaoying Wang a,c, Han Zhang b,c, Lili Chen b,c, Lihua Shan a, Guanwei Fan b,c, Xiumei Gao b,c,n a College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China b Institute of Traditional Chinese Medicine Research, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China c Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin 300193, China article info abstract Article history: Ethnopharmacological relevance: Liquorice is the root of Glycyrrhiza uralensis Fisch. or Glycyrrhiza glabra L., Received 23 June 2013 Leguminosae. It is a widely used herbal medicine native to southern Europe and parts of Asia and has Received in revised form beneficial applications in both the medicinal and the confectionery sectors. Unlike its usage in Europe, 24 September 2013 liquorice in traditional Chinese medicine is commonly combined with other herbs in a single prescription, Accepted 24 September 2013 as a unique “guide drug” to enhance the effectiveness of other ingredients, to reduce toxicity, and to Available online 5 November 2013 improve flavor in almost half of Chinese herbal formulas. A review on phytochemical and pharmacological Keywords: research to explain this unique “guide” effect is suggested for future investigations. Liquorice Materials and methods: The information was collected from scientific journals, books, and pharmacopeia. The Cytochrome P450 studies about the traditional uses, randomized controlled trials, chemical, pharmacological and pharmaco- Drug interactions kinetic data related to liquorice–herb/drug interaction or combination were included in the review. Traditional Chinese medicine Results: According to recent reports, the “guide” effect of liquorice is partially through components Detoxification 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 investi- gations and clinical use, especially in drug combination. & 2013 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction . 782 2. Liquorice in TCM theories . 782 3. Modern pharmacological experiments and clinical trials of liquorice. 782 4. Component analysis in liquorice–drug interaction . 783 5. The effects of liquorice and its active components on model probe substrates of CYP isoforms . 785 6. The effects of liquorice/active ingredients on drug transporter proteins . 786 7. Adverse effects and toxicological studies of liquorice . 788 8. Conclusions . 788 Acknowledgements . 788 References.............................................................................................................788 Abbreviations: CYP, cytochrome; DGLL, diammonium glycyrrhizinate lipid ligand; GA, glycyrrhetic acid; GZ, glycyrrhizin; HSYA, hydroxysafflor yellow A; IC50, half maximal inhibitory concentration; P-gp, P-glycoprotein; TCM, traditional Chinese medicine n Corresponding author at: Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin 300193, China. Tel.: þ86 22 59596586. E-mail address: [email protected] (X. Gao). 0378-8741/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2013.09.055 782 X. Wang et al. / Journal of Ethnopharmacology 150 (2013) 781–790 1. Introduction liquorice is based on the ability to tonify the qi (life energy) of the heart and spleen. Liquorice is also useful for relieving the follow- Herbal products are becoming popular as alternative medicines ing conditions: phlegm, cough, dyspnea, spasms, pain, and toxicity worldwide. Herb–drug and herb–herb interactions are a current and cooperates with other medicines. As a tonic herbal medicine topic of debate, while combination therapies have been validated in TCM, liquorice is a high-grade herb, non-toxic and sweet, and it and show potential clinical benefits. Traditional Chinese Medicine is slightly “cold” in nature. It is combined in various formulas due (TCM) has focused on this issue because most herbs are combined to its ability to harmonize the characteristics of other herbs. with others in a single prescription. The most notable of these is Through detoxification, it can reduce the toxic properties of certain liquorice (Glycyrrhiza), which appears in approximately 60% of herbs. Through harmonizing, it can improve the synergy between TCM prescriptions (Xing et al., 2011). “cold” and “heat” herbs in a formula, alleviate the toxicity of herbs, Liquorice (Radix Glycyrrhizae, Liquiritiae radix) is the root of and modulate the taste of herbs due to its sweet flavor. Glycyrrhiza uralensis Fisch. or Glycyrrhiza glabra L. or Glycyrrhiza After the mention of liquorice in Shen Nong Ben Cao Jing, all inflata Bat., Leguminosae. It is a widely used herbal medicine subsequent TCM literature describes liquorice as an essential herb native to southern Europe and parts of Asia and has beneficial with a variety of usages. In 283 herbal prescriptions in “Shang Han applications both in the medicinal and the confectionery sectors. Za Bing Lun” (which is among the oldest complete clinical text- The sweet-tasting compound makes the liquorice root in popular books in the world and compiled by Zhang Zhongjing prior to 220 candies or sweets in Europe, and meanwhile a history of its A.D.), liquorice was used in 140 formulas. In Tai Ping Hui Min He Ji various therapeutic applications also has been documented Ju Fang, the first official formula book in China (Song Dynasty, 960- (Fiore et al., 2005). Unlike its usage in Europe, in China, liquorice 1279), liquorice appeared in 261 prescriptions among 788 listed is one of the most widely used herbal medicines, as it appears in herbal formulae. Therefore, classical texts state that “nine out more than half of TCM prescriptions. According to TCM theory, of ten herbal formulas contain liquorice” (Wang et al., 2002). liquorice is primarily effective for fatigue and debilitation, asthma A summary of historical references having important formulas that with coughing, excessive phlegm and for relieving drug toxicity. contain liquorice is shown in Table 1. Moreover, it has a unique effect on moderating and complement- We analyzed the frequency of herbs that were combined with ing the characteristics of other herbs, leading to a special guide liquorice in Shang Han Za Bing Lun. The ten herbs with the highest role in many Chinese herbal prescriptions (Commission, 2010). frequencies are the following: Fructus jujubae (Da Zao, 63 times), Unlike European herbal medicine, in which herbs are often Ramulus Cinnamomi (Gui Zhi, 63 times), Rhizoma Zingiberis used alone, TCM uses several herbs in one prescription. According Recens (Sheng Jiang, 60 times), Radix Paeoniae Alba (Shao Yao, to the theories of TCM, the prescriptions are classified as monarch 43 times), Herbal Ephedrae (Ma Huang, 28 times), Radix Ginseng (main) drugs, minister drugs, assistant drugs, and guide drugs (Ren Shen, 27 times) Rhizoma Pinelliae (Ban Xia, 26 times), (Steven and Yue, 1992). Monarch drugs are those that exert the Rhizoma Zingiberis (Gan Jiang, 26 times), Radix Aconiti Lateralis primary effect on the health condition. Assistant drugs cooperate Praeparata (Fu Zi, 20 times), Poria (Fu Ling, 17 times), and Gypsum with the major ingredient in a prescription to enhance its effect. Fibrosum (Shi Gao, 17 times), which comprised approximately 50% Minister drugs synergistically increase the effect of the monarch of the drugs combined with liquorice (Fig. 1). Of these top ten drug. Meanwhile, the "guide drug" is added to enhance the herbs, six are warm in nature, and two are hot in nature which effectiveness of other ingredients, to reduce toxicity or to improve refers medicine's effect on our bodies. In TCM theory, all medicinal taste. Although it has multiply pharmacological effects, liquorices are ascribed a nature, cold, cool, neutral, warm, or hot. “Cool” and is more commonly used as a unique “guide drug” in more than half “cold” herbs treat heat diseases like high fever, strong sweating, of all traditional and modern formulas and prescriptions, which and big thirst. “Warm” and “hot” herbs treat cold diseases like cold accounts for its unique effect on moderating the characteristics of limbs, aversion to cold, watery diarrhea (Ergil and Ergil, 2009). other herbs in low dosages (Wang and Gong, 2013). The moderat- According to TCM theory, “warm”/“hot” drugs are more likely than ing effects of liquorice on other herbs include a marked detoxify- “cold” drugs to lead to serious adverse reactions of the respiratory ing effect that can treat drug and food poisoning and/or inhibit system and to cause cardiovascular damage. “Hot” drugs, such as adverse effects, and this “guide” effect has been examined in a Rhizoma Zingiberis and Radix Aconiti Lateralis Praeparata, are number of formulas