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Abstract

Licorice is a traditional medicine commonly used in China and many other countries. Over the last 50 years, the structure and pharmacological effects of coumarin compounds in licorice have been investigated. However, a comprehensive review of the literature summarizing current trends is currently lacking. Thus, the aim of the present review is to provide an up-to-date summary of the scientific literature regarding the pharmacological effects of coumarin compounds in licorice, thereby laying the foundation for further research and optimal utilization of licorice. We retrieved 111 articles on the coumarin components of licorice and their potential pharmacological effects, based on titles, keywords, and abstracts from databases (including PubMed and Web of Science). Glycycoumarin, isoglycycoumarin, licoarylcoumarin, licopyranocoumarin, glycyrin, isotrifoliol, glycyrol, and glycyrurol have been investigated for their anticancer, hepatoprotective, antispasmodic, immunosuppressive, anti-inflammatory, and antibacterial properties, and use as therapeutic agents in metabolic syndrome, thereby demonstrating their potential for clinical applications. Future research should further explore the pharmacological mechanisms of action of coumarin compounds, including their antibacterial activities. Investigations into the pharmacological activities of different glycycoumarin isomers might open new research frontiers.

Keywords

licorice coumarins pharmacological activities glycycoumarin glycyrol

Introduction

Licorice, or Gan-Cao in Chinese, is derived from the roots and rhizomes of Glycyrrhiza uralensis Fisch., G. inflata Bat., and G. glabra L.^1,2 Licorice is an ancient Chinese ethnomedicine and its traditional benefits include tonifying the spleen and stomach, relieving pain, reducing phlegm, alleviating cough, and detoxification.^3,4 Currently, licorice is used in many countries for the treatment of various digestive ailments (eg, stomach ulcers, hyperdipsia, flatulence, and colic), respiratory tract disorders (eg, coughs, sore throat, pneumonia, bronchitis, and bronchial asthma), fluid retention, low blood pressure, sexual debility, paralysis, rheumatism, psoriasis, malaria, jaundice, and certain viral infections.^5
-7

Coumarins are benzopyrone analogs that are secondary metabolites of many plant species, including those from the Clusiaceae, Umbelliferae, Rutaceae, and Leguminosae families.^8,9 Coumarins such as novobiocin, coumermycin, and aflatoxin, have also been identified in bacteria and fungi.^10,11 In addition, coumarins and their hybrids can be rationally designed and produced and their derivatives synthesized via Perkin condensation, Knoevenagel condensation, the Pechmann reaction, and metal-catalyzed cyclization.^12
-14 Based on their structural diversity, compounds in this family have been divided into various categories, including simple coumarins and polycyclic coumarins such as furocoumarins, pyranocoumarins, and phenylcoumarins.^12,15

Coumarins and coumarin-based hybrids have demonstrated numerous biological properties, including anticancer,^16,17 anti-inflammatory,^18,19 antioxidant,^20,21 antiviral,^22,23 antimicrobial,^17,24,25 antifungal,²⁶ antitubercular,²⁷ anticoagulant,²⁸ antispasmodic,²⁹ antihyperglycemic,³⁰ antitubulin,^31,32 immunosuppressive,^33,34 hepatoprotective,³⁵ and neuroprotective³⁶ activities. Some mechanistic studies have also been performed. For example, coumarins have been evaluated as mitogen-activated and extracellular signal-regulated kinase inhibitors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitors, and nucleotide excision repair inhibitors that interfere with cell growth, proliferation, differentiation, and other important cellular processes. Thus, their activity has been associated with tumorigenesis.¹⁵ Coumarins and their derivatives also exhibit antimicrobial activities by blocking quorum-sensing signaling systems and inhibiting the formation of biofilms.²⁵ The antioxidant action of some coumarins is dependent on the benzylic hydrogen atoms; the resonance involving these atoms promotes the release of hydrogen as a free radical, whereas the inductive effect of the benzene ring, oxygen, and nitrogen draws electrons to form a carbon-free radical, enhancing the stability of the molecule.³⁷ The antiviral mechanisms of some coumarins involve either the inhibition of proteins essential for viral entry, replication, and infection, or the regulation of cellular pathways such as the Akt-mammalian target of rapamycin, NF-κB, and antioxidant pathways, which include nuclear factor erythroid 2-related factor 2 (Nrf2).

Licorice contains various naturally active compounds including flavonoids, triterpenoid saponins, coumarins, and phenolics. Of these, coumarins are one of the most important natural organic compounds.^38
-40 Since glycyrol and isoglycyrol were first separated from Glycyrrhiza spp. in 1969,⁴¹ their structures and pharmacological effects, as well as those of other licorice-coumarin compounds, have been gradually elucidated. Coumarin compounds in licorice possess different structures and include simple coumarins (liqcoumarin³⁸), 3-arylcoumarins (glycycoumarin,⁴² isoglycycoumarin,⁴³ licoarylcoumarin,⁴⁴ 7,2′,4′-trihydroxy-5-methoxy-3-arylcoumarin,⁴⁵ licopyranocoumarin [also known as GU-7],^46,47 glycyrin,⁴⁸ and licofuranocoumarin⁴⁹), coumestans (isotrifoliol,⁴⁹ glycyrol,⁴¹ isoglycyrol,⁴¹ neoglycyrol,⁵⁰ glycyrurol,⁵¹ gancaonin-F,⁵² hedysarimcoumestan B,⁴⁵ hedysarimcoumestan E,⁴⁵ and sophoracoumestan C⁵³), and 4-arylcoumarin (inflacoumarin A⁵⁴). Among these, glycycoumarin, isoglycycoumarin, licopyranocoumarin, isotrifoliol, glycyrol, glycyrurol, licoarylcoumarin, and glycyrin are the major coumarin components; their structures are presented in Figure 1.

Figure 1

Structures of 8 major coumarin compounds in licorice.

Previously reported studies on the pharmacological effects of 8 coumarin compounds (glycycoumarin, isoglycycoumarin, licoarylcoumarin, licopyranocoumarin, glycyrin, isotrifoliol, glycyrol, and glycyrurol) were identified using available online scientific databases such as PubMed and Web of Science, without a time restriction. The names of coumarin compounds in licorice, including “glycycoumarin” and “glycyrol,” were combined with words related to their pharmacological actions, including “anti-inflammatory” and “anticancer,” and searched in titles, keywords, and abstracts. The methods of biosynthesis, metabolic reactions, and coumarin products were not within the scope of this analysis. In addition, papers on compound medicines with an unclear chemical composition were excluded. Using this search strategy, 156 articles between 1964 and 2020 were identified, of which 45 were excluded. The pharmacological effects mentioned in the 111 articles included in this review are shown in Table 1. This review summarizes the findings of both in vivo and in vitro studies on coumarins from licorice.

Table 1

Coumarin Compounds in Licorice and Their Activities.

Compound in licorice	Activity
Glycycoumarin	Anticancer, hepatoprotective, antispasmodic, therapeutic activities toward metabolic syndrome, anti-inflammatory, neuroprotective, antimicrobial, antioxidant, antiviral, estrogenic
Isoglycycoumarin	Selective probe
Licopyranocoumarin	Neuroprotective, antiviral, antiplatelet
Isotrifoliol	Antithrombotic
Glycyrol	Anticancer, hepatoprotective, therapeutic activities toward metabolic syndrome, immunosuppressive, anti-inflammatory, antimicrobial, antiviral, treating acute lung injury
Glycyrurol	Neuroprotective
Licoarylcoumarin	Antimicrobial
Glycyrin	Therapeutic activities toward metabolic syndrome, antimicrobial, antiviral

Anticancer Activities

The anticancer activity of glycyrol was first reported in 2007,⁵⁵ when it was demonstrated to dose-dependently decrease the viability of human gastric cancer cells (AGS and SNU638 cells). However, its mechanism of action was not determined at that time. Glycyrol was later found to induce apoptosis in human kidney epithelial 293 T cells (HEK 293 T cells) through endonuclease G.⁵⁶ Glycyrol can significantly suppress the NF-κB-dependent transcriptional activity induced by phorbol ester (phorbol 12-myristate 13-acetate), as determined using luciferase reporter activity in HEK 293 T cells. Glycyrol also induces apoptosis by activating p53 through endonuclease G.

Another study revealed that glycyrol induces apoptosis in human Jurkat cells through a membrane death receptor pathway that is independent of p53.⁵⁷ This indicates that glycyrol induces the apoptosis of human Jurkat cells by NF-κB inhibition, S-phase arrest, caspase activation, and Fas enhancement, but not via either Bcl-2 or Bax proteins.

The anticancer activity of glycyrol, both in vitro and in vivo, was first evaluated in 2014,⁵⁸ when it was found to induce cell death associated with apoptosis and autophagy, as evidenced by morphological changes in AGS and HCT-116 cells. In addition, glycyrol has been shown to suppress tumor growth in a nude mouse tumor xenograft model bearing HCT-116 cells.

Butyrate has been shown to exert anticancer activity by inducing apoptosis and inhibiting the growth of colon cancer cells.^59,60 Lu et al⁶¹ attempted to combine butyrate with glycyrol to reduce the proliferation of cancer cells. These results demonstrated that the combination greatly enhanced the apoptotic effect of butyrate owing to the benzofuranyl, isopentenyl, and furan groups of glycyrol.

Wang et al⁶² showed that glycyrol exerts higher cytotoxicity than liquiritcoumarin, crotoliquiritin, ammopiptanoside A, glycyrin, hedysarimcoumestan B, glycyrrhisoflavone, licoisoflavone A, isolicoflavonol, licoflavonol, isoliquiritigenin, licochalcone, licoricone, and glabrol. Glycyrol exhibits a moderate antiproliferative effect with a half-maximal inhibitory concentration (IC₅₀) of 11.46 μM for A549 cells and 7.38 μM for NCI-H292 cells, following treatment for 48 hours; however, the underlying mechanism for this effect was not determined.

Glycycoumarin, another coumarin component extracted from licorice, was found to exert potent antihepatoma effects, as demonstrated through the induction of apoptosis in vitro (HepG2, Huh7, DU-145, and HCT-116 cells) and reduction of tumor size in vivo (male BALB/c athymic nude mice).⁶³ The treatment of HepG2 cells with glycycoumarin for 36 hours leads to a concentration-dependent increase in cell death.

ABT-737 is an inhibitor of the Bcl-2 family of proteins that leads to the disruption of mitochondrial membrane potential.⁶⁴ The protective effects of glycycoumarin inhibited ABT-737-mediated toxicity of platelets against liver cancer significantly in both cell culture and xenograft animal models.

The specific mechanisms underlying the anticancer activities of these coumarin compounds are shown in Table 2.

Table 2

Summary of Studies Investigating the Anticancer Activities of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	Reference
Anticancer (gastric)	Glycyrol	AGS and SNU638 cells	In vivo	Not determined	⁵⁵
Apoptosis of tumor cells (kidney)	Glycyrol	HEK 293 T cells	In vitro	Downregulation of NF-κB-dependent genes; inducing apoptosis through activation of p53 via endonuclease G	⁵⁶
Apoptosis of human Jurkat T cells	Glycyrol	Human Jurkat T lymphocytes	In vitro	Enhanced cleavage of procaspases-8, 9, and 3, and decreased caspase-3 activity	⁵⁷
Apoptosis of tumor cells (gastric, kidney)	Glycyrol	Human gastric cancer AGS; human colon cancer HCT-116 cells	In vitro; in vivo	Induction of G0/G1 phase arrest by increasing p21; activation of JNK/p38 MAPKs and induction of caspase-dependent apoptosis, accompanied by AMPK activation	⁵⁸
Anticancer (colon)	Glycyrol	Human colon cancer cells HCT-116, HT-29	In vitro	Suppression of IAPs, combined with butyrate-induced mitochondrial pathway leading to the synergistic induction of cell death	⁶¹
Cytotoxicity	Glycyrol	A549 cells and NCI-H292 cells	In vitro	Not determined	⁶²
Anticancer (liver)	Glycycoumarin	Human hepatocellular carcinoma cells HepG2, Huh7, and human prostate cancer DU-145 cells; human colon cancer HCT-116 cells; male BALB/c athymic nude mice	In vitro; in vivo	Binds to and inactivates oncogenic TOPK, leading to activation of the p53 pathway	⁶³
Anticancer (liver)	Glycycoumarin	HepG2, Huh-7, and SMMC-7721 cells; HepG2 xenograft mice	In vitro; in vivo	Inactivates the TOPK-survivin axis and inhibits de novo lipogenesis	⁶⁴

Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; IAPs, inhibitors of apoptosis proteins; JNK, c-Jun N-terminal kinase; MAPKs, mitogen-activated protein kinases;NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TOPK, T-LAK cell-originated protein kinase.

Hepatoprotective Activities

Recent studies have used glycycoumarin to ameliorate alcoholic liver disease, combat acetaminophen-induced acute liver injury (AILI), and prevent the development of nonalcoholic fatty liver disease (NAFLD).

Glycycoumarin exerts a strong preventive effect against alcohol-induced hepatotoxicity in mouse models of chronic and acute alcohol-induced liver injury. However, a study found a clear decrease in steatosis induced by chronic alcohol exposure following co-treatment with glycycoumarin and alcohol.⁶⁵

Another study demonstrated that glycycoumarin (50 mg/kg) is effective in acetaminophen-induced hepatotoxicity in C57BL/6N mice. AILI is dose-dependently ameliorated following treatment with glycycoumarin, as demonstrated by a progressive reduction in the serum levels of alanine aminotransferase. Moreover, glycycoumarin is superior to N-acetylcysteine, a modified amino acid clinically used as the only standard treatment for AILI, in terms of effective dosage and therapeutic time window.⁶⁶

Two later studies^67,68 revealed that glycycoumarin could effectively prevent NAFLD by suppressing endoplasmic reticulum (ER) stress and inducing lipoapoptosis. In in vitro models, treatment with 10-40 μM glycycoumarin was found to suppress apoptosis significantly in HepG2 cells; at 20 μM, and it was highly effective in preventing oleic acid/palmitic acid-induced lipid accumulation.⁶⁷ In in vivo models, glycycoumarin reverses the biochemical and pathological changes in methionine/choline-deficient diet-fed mice, such as a marked increase in alanine transaminase, a key marker of liver injury, and the accompanying profound hepatic steatosis. In addition, glycycoumarin leads to a reduction in body weight.⁶⁸ In a recent study by the same group, glycyrol was also found to suppress fumonisin B1 (FB1)-induced ER stress and protect against apoptosis via the inactivation of inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α).⁶⁹ Glycyrol (10 μM) significantly reduces the apoptosis of AML12 cells following exposure to 300 μM FB1 for 48 hours. Furthermore, FB1-induced IRE1α phosphorylation and Bip upregulation are suppressed following treatment with glycyrol at this concentration for 24 hours (P < 0.01).

The specific mechanisms underlying the hepatoprotective activities of these coumarin compounds are presented in Table 3.

Table 3

Summary of Studies Investigating the Hepatoprotective Activities of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	References
Amelioration of alcoholic liver disease	Glycycoumarin	C57BL/6J mice, mouse hepatocyte AML-12 cells, human hepatocellular carcinoma HepG2 cells	In vivo; in vitro	Activation of Nrf2 via the p38 pathway and induction of autophagy, contributing to hepatoprotective activity	⁶⁵
Combating acetaminophen-induced acute liver injury	Glycycoumarin	Male C57BL/6 mice; Nrf2-KO mice on a C57BL/6J background	In vitro	Sustained activation of autophagy, which in turn attenuates acetaminophen-induced mitochondrial oxidative stress and JNK activation	⁶⁶
Prevention of nonalcoholic fatty liver disease	Glycycoumarin	HepG2 cells; male C57BL/6 mice	In vivo; in vitro	Reactivation of impaired autophagy by lipid metabolic disorders; inhibition of ER stress-mediated JNK and mitochondrial apoptotic pathway activation; activation of AMPK-mediated lipophagy; inhibition of lipogenesis and enhanced fatty-acid oxidation	^67,68
Inhibition of hepatotoxicity	Glycyrol	AML-12 mouse liver cells	In vivo; in vitro	Protection against fumonisin B1-induced ER stress-mediated hepatotoxicity via the activation of the IRE1α-JNK-mitochondria pathway	⁶⁹

Abbreviations: AMPK, adenosine monophosphate-activated protein kinase;ER, endoplasmic reticulum; JNK, c-Jun N-terminal kinase; KO, knockout; Nrf2, nuclear factor erythroid 2-related factor 2.

Antispasmodic Activities

The antispasmodic activity of the coumarin compounds found in licorice can help control abdominal cramping, fecal urgency, and postprandial lower-abdominal discomfort associated with diarrhea.⁷⁰

Glycycoumarin was found to inhibit contractions induced by various types of stimulants, including carbachol, potassium chloride, barium chloride, and A23187 (calcium ionophore III), with similar efficacy as papaverine, a representative antispasmodic drug targeting the smooth muscle.⁷¹ In addition, the antispasmodic potency of cultivated and wild licorice was found to be directly dependent on glycycoumarin content, according to a study published by Nagai et al.⁷² They also reported that boiled-water extracts from 4-year-old cultivated and wild licorice exerted relaxant activity on carbachol-induced contractions in mouse jejunum (median effective dose: 134 ± 21 and 134 ± 16 μg/mL, respectively). However, the mechanism of action underlying this activity was not determined.

Shaoyaogancao-tang, a formulation that contains powdered extracts of the roots and rhizomes of licorice,⁷¹ is prescribed to provide rapid relief of muscle cramps arising from different causes.^73

-77 Researchers found that a low intravenous dose (2.7 mmol/kg) of glycycoumarin (1 of 8 active constituents) attenuated tetanus-induced contractions by 15%-22% (30-60 minutes) after administration.⁷⁸ At a higher intravenous dose (27 mmol/kg), it significantly and more rapidly reduced the amplitude of tetanus-induced contractions by 17%-24% (10-60 minutes) after administration, displaying a long-lasting inhibitory effect. The specific mechanisms underlying the antispasmodic activities of these coumarin compounds are shown in Table 4.

Table 4

Summary of Studies Investigating the Antispasmodic Activities of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanisms of action	References
Inhibition of contraction	Glycycoumarin	Male ICR mice	In vivo	Inhibits smooth muscle contraction induced by various types of stimulants by inhibiting phosphodiesterases, especially isozyme 3, resulting in the accumulation of intracellular cyclic adenosine monophosphate	⁷¹
Relaxant activity	Glycycoumarin	1 cm segment of jejunum isolated from male ICR mice	In vitro	Not determined	⁷⁰
Depressed amplitude of tetanic contraction	Glycycoumarin	Male Wistar mice	In vivo	Suppressed Ca²⁺-induced concentrations to exert antispasmodic effects, thus ameliorating muscle cramps	⁷⁸

Therapeutic Activities Toward Metabolic Syndrome

Metabolic syndrome refers to a cluster of conditions that occur simultaneously and increase the risk of heart disease, stroke, and type 2 diabetes.⁷⁹ Ligands, such as those targeting peroxisome proliferator-activated receptor (PPAR)-γ, are effective in metabolic syndrome, including type 2 diabetes.⁸⁰ Glycycoumarin, glycyrin, dehydroglyasperin C (flavonoid), and dehydroglyasperin D (flavonoid) have been reported as PPAR-γ ligands.^81,82 When these were mixed at the same concentrations found in licorice ethanolic extract, the effective PPAR-γ ligand-binding activity was found to be 90% of the extract-binding activity.⁸¹

Glycyrin markedly reduces blood glucose levels in genetically diabetic KK-Ay mice. In addition, glycyrin exhibits significant PPAR-γ ligand-binding activity in vitro. However, after 4 days of feeding, the blood glucose levels of glycyrin-treated and pioglitazone-treated animals were markedly reduced relative to those in the control group. In an oral sucrose tolerance test, glycyrin and pioglitazone significantly inhibited the increase in blood glucose levels in mice after sucrose loading.⁸³

The specific mechanisms underlying the therapeutic activities of these coumarin compounds on metabolic syndrome are shown in Table 5.

Table 5

Summary of Studies Investigating the Therapeutic Activities of Coumarin Compounds From Licorice on Components in Metabolic Syndrome.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanisms of action	References
Prevention of diabetes, abdominal obesity, and hypertension	Glycycoumarin, glycyrin	CV-1 monkey kidney cells; female genetically diabetic KK-Ay/Ta mice	In vivo; in vitro	PPAR-ligand-binding activity; inhibition and reduction of visceral fat accumulation, similar to thiazolidinediones	^81,82
Reduction in blood glucose	Glycyrin	CV-1 monkey kidney cells; female KK-Ay mice	In vivo; in vitro	Significant PPAR-γ ligand-binding activity and reduced blood glucose levels in diabetic KK-Ay mice	⁸³

Abbreviation: Abbreviation: PPAR, peroxisome proliferator-activated receptor.

Immunosuppressive and Anti-Inflammatory Activities

Calcineurin (CN) is a protein phosphatase that plays an important role in immune regulation.⁸⁴ Glycyrol (IC₅₀ = 84.6 μM) was found to dose-dependently inhibit CN activity in an enzymatic assay.⁸⁵ At a noncytotoxic concentration, glycyrol markedly reduced the proliferation of murine splenic T lymphocytes induced by concanavalin A and the mixed lymphocyte reaction. The delayed hypersensitivity (DTH) of glycyrol-treated mice decreased in a dose-dependent manner, whereas graft survival (BALB/c mice with skin grafts from male donor C57BL/6 mice) increased by 59% compared with that of the control group (P < 0.05). Another study examined the interaction between glycyrol with calcineurin A (CNA)⁸⁶ and demonstrated that glycyrol binding changes the secondary structure of CNA, which may inhibit CN activity.

Glycyrol has also been shown to induce autoimmune regulation and inflammatory responses. A study demonstrated that the anti-inflammatory effect of glycyrol is caused by the inhibition of nuclear factor-kappa B alpha (IκBα) phosphorylation.⁸⁷ However, another study reported that the peroral administration of glycyrol is effective in slowing down collagen-induced arthritis in male DBA/1J mice, a model of rheumatoid arthritis, as it decreases serum inflammatory cytokine levels.⁸⁸ Glycyrol reduces DTH, improves carbon clearance and decreases acetic acid-induced capillary permeability.

Glycycoumarin is another coumarin constituent that exerts anti-inflammatory activity.⁸⁹ This compound inhibited prostaglandin E2 (PGE2) secretion by more than 80% at a concentration of 10 μM in RAW 264.7 murine macrophages.

Glycycoumarin and glycyrol are 2 of the main compounds in San′ao decoction (SAD), an extract formulation prescribed for the treatment of asthma.⁹⁰ The ethyl acetate fraction of SAD has a dramatic effect on PPAR-γ activation and may have anti-inflammatory properties during various chronic inflammatory processes. Glycycoumarin (5 μM) also exerted significant activity on PPAR-γ; however, this was found to be less than that of formononetin in the SAD ethyl acetate fraction. The specific mechanisms underlying the immunosuppressive and anti-inflammatory activities of these coumarin compounds are shown in Table 6.

Table 6

Summary of Studies Investigating the Immunosuppressive and Anti-Inflammatory Activities of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	Reference
Immunosuppressive activity	Glycyrol	Jurkat cells; BALB/c mice; C57BL/6 mice	In vitro; in vivo	Suppression of IL-2 production in a concentration-dependent manner; regulation of T lymphocytes	⁸⁵
Immunosuppressive activity	Glycyrol	CNA; CNAabc; CNAab; CNAa; CNA-W134; CNA-W232; CNA-W342; CNA-W352	Molecular model	Binds to calcineurin A via hydrophobic interactions in a 1:1 ratio at the catalytic domain close to the calcineurin B subunit-binding domain	⁸⁶
Anti-inflammatory activity	Glycyrol	Male ICR mice; RAW264.7 macrophages	In vivo; in vivo	Inhibition of nitric oxide production by downregulating inducible nitric oxide synthase and reducing expression of cyclooxygenase-2 in LPS-stimulated RAW264.7 macrophages; decreased messenger ribonucleic acid expression of the proinflammatory cytokines IL-1β and IL-6; prevention of LPS-induced NF-κB activation via inhibition of nuclear factor kappa B alpha phosphorylation	⁸⁷
Regulation of autoimmune and inflammatory responses	Glycyrol	Male DBA/1J mice	In vivo	Decreased transcriptional activities of NF-κB and NFAT; inhibition of IL-2 expression to downregulate autoimmune and inflammatory reactions	⁸⁸
Anti-inflammatory activity	Glycycoumarin	RAW 264.7 murine macrophages	In vivo	Inhibition of NO, IL-6, and prostaglandin E2 production in LPS-induced macrophages	⁸⁹
Anti-inflammatory activity	Glycycoumarin; glycyrol	Chinese hamster ovary cell line	In vitro	Activation of peroxisome proliferator-activated receptor-γ and subsequent NF-κB inhibition	⁹⁰

Abbreviations: CNA, calcineurin A; IL, interleukin; LPS, lipopolysaccharide; NFAT, nuclear factor of activated T cells;NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide.

Neuroprotective Activities

Licorice has been shown to possess protective effects against amyloid β (Aβ) oligomer-induced apoptosis.⁹¹ This study also demonstrated that glycycoumarin markedly reduced Aβ oligomer-induced neuronal death at concentrations of 10, 30, and 50 mM (F [6, 35] = 64.584, P < 0.001).

Parkinson’s disease is a neurodegenerative disease characterized by the progressive death of dopaminergic neurons in the substantia nigra. Licopyranocoumarin and glycyrurol have demonstrated cytoprotective effects in neuronal cells. These compounds block 1-methyl-4-phenylpyridinium (MPP+)-induced neuronal PC12D cell death and the loss of mitochondrial membrane potential, which are mediated by c-Jun N-terminal kinase.⁹²

The specific mechanisms underlying the neuroprotective activities of these coumarin compounds are shown in Table 7.

Table 7

Summary of Studies Investigating the Neuroprotective Activities of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	Reference
Amyloid β oligomer-induced apoptosis	Glycycoumarin	Sprague-Dawley rat embryos	In vivo	Attenuation of amyloid β oligomer-induced activation of caspase-3, but not caspases-8 and 9	⁹¹
Cytoprotective treatment for Parkinson’s disease	Licopyranocoumarin and glycyrurol	PC12 pheochromocytoma cells	In vitro	Inhibition of reactive oxygen species generation and the subsequent suppression of MPP+-induced JNK activation; attenuation of MPP+-induced neuronal PC12D cell death	⁹²

Abbreviations: JNK, c-Jun N-terminal kinase; MPP, 1-methyl-4-phenylpyridinium.

Antimicrobial Activities

Glycycoumarin was first reported to exert activity against microorganisms including bacteria, yeast, and fungi, in 1988.⁹³ Approximately, 13 years later, a study revealed that glycyrol, glycyrin, and glycycoumarin display antibacterial activity against Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, and other bacteria of the upper respiratory tract.⁹⁴ The minimum inhibitory concentrations (MICs) of these 3 compounds against microorganisms are listed in Table 8. A previous study showed that glycyrin has weak activity against Helicobacter pylori, similar to that reported for glycyrrhetinic acid and liquiritigenin.⁹⁵ Eerdunbayaer et al found that licoarylcoumarin and glycycoumarin have moderate antibacterial activity toward vancomycin-resistant Enterococci.⁹⁶ Low MIC values (16 μg/mL) were found for Enterococcus faecium and Enterococcus faecalis via the liquid dilution method. However, the mechanisms underlying the antimicrobial activity were not elucidated in the above-mentioned studies.

Table 8

Minimum Inhibitory Concentrations (MICs; μg/mL) of 3 Licorice Constituents Tested Against Microorganisms.^93,94

Substance	Glycycoumarin	Glycyrol	Glycyrin
Bacteria
Streptococcus mutans	12.5	-	-
Staphylococcus aureus	3.13	-	-
Bacillus subtilis	6.25	-	-
Streptococcus pyogenes	25	50	50
Haemophilus influenzae	25	100	20
Moraxella catarrhalis	100	>100	50
Yeasts
Saccharomyces cerevisiae	25	-	-
Candida utilis	50	-	-
Pichia nakazawae	25	-	-

Note: “-” Denotes not determined.

In 2015, a study revealed that activity-guided compounds from G. glabra significantly decreased the virulence factor of Acinetobacter baumannii, including motility (P < 0.05), which regulates quorum sensing and the production of antioxidant enzymes.⁹⁷ Glycyrin was also identified as a coumarin compound responsible for quorum quenching against A. baumannii. Another study found that glycyrin extracted from G. glabra possessed activity against Bacillus subtilis FtsZ (BsFtsZ) guanosine triphosphate (GTPase), with efficacy levels similar to those reported for the synthetic FtsZ inhibitor, Zantrin Z3.⁹⁸ Only 1 in vivo experiment involving coumarin in licorice indicates that glycyrol may contribute to the development of a novel agent with antifungal activity against cutaneous candidiasis.⁹⁹ The comparison of infected sites on the dorsal sides of treated and untreated mice showed that glycyrol treatment of the infected sites reduced colony-forming units by up to 60% and 85.5% at 20 and 40 μg/mouse of glycyrol, respectively (P < 0.01). To the best of my knowledge, coumarins from licorice are safe for human consumption, but a thorough analysis of their potential cytotoxicity has not been performed to date. Two of the studies mentioned above have reported underlying mechanisms of action of coumarin compounds, whereas the other studies have not demonstrated any mechanism, as summarized in Table 9.

Table 9

Summary of Studies That Investigated the Activity of Licorice-Based Coumarin Compounds Against Microorganisms.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	References
Antimicrobial activity	Glycycoumarin	Microorganisms listed in Table 8	In vitro	-	⁹³
Antibacterial activity against upper respiratory tract pathogens	Glycyrol, glycyrin, and glycycoumarin	Streptococcus pyogenes, Haemophilus influenza, and Moraxella catarrhalis	In vitro	-	⁹⁴
Inhibition of Helicobacter pylori activity	Glycyrin	H. pylori ATCC 43504, ATCC 43526, H. pylori ZLM 1007, ZLM 1200, clarithromycin-resistant H. pylori GP98	In vitro	-	⁹⁵
Inhibition of Enterococcus species activity	Licoarylcoumarin and glycycoumarin	E. faecium FN-1 and E faecalis NCTC 12201	In vitro	-	⁹⁶
Attenuation of quorum sensing-mediated virulence of Acinetobacter baumannii	Glycyrin	Acinetobacter baumannii strains and Acinetobacter tumefaciens A136	In vitro	Reduced expression of the autoinducer synthase gene, abaI, and decreased production (92%) of 3-OH-C12-HSL	⁹⁷
Inhibition of Bacillus subtilis FtsZ (BsFtsZ) GTPase activity	Glycyrin	Plasmid DNA encoding BsFtsZ, EcFtsZ, and the BsFtsZ V307R mutant protein	In vitro	Binds to the cleft on BsFtsZ as an uncompetitive FtsZ inhibitor, PC190723; anti-BsFtsZ inhibitory activity	⁹⁸
Inhibition of Candida albicans activity	Glycyrol	BALB/c female mice; C. albicans yeast cells	In vivo and in vitro	Damages the cell wall to enhance the response of C. albicans to fluconazole	⁹⁹

Abbreviation: Abbreviation: 3-OH-C12-HSL, N-(3-hydroxydodecanoyl)-L-homoserine lactone.

“-” Denotes not determined.

Antioxidant Activities

A previous study has indicated that some coumarin compounds possess the significant antioxidant ability for scavenging peroxyl radicals in experiments involving reactive oxygen species.¹⁰⁰

The first study to report the antioxidant activity of glycycoumarin derived from licorice also elucidated its antimicrobial activity.⁹³ However, the data indicate that the peroxidase activity of glycycoumarin is close to that of the blank control, suggesting that glycycoumarin does not exert significant peroxidase activity. Nevertheless, another study revealed that glycycoumarin has strong scavenging activity against 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)⁺ radicals and could inhibit lipid peroxidation in rat liver microsomes relative to ascorbic acid.¹⁰¹ The specific mechanisms underlying the antioxidant activities of these coumarin compounds are shown in Table 10.

Table 10

Summary of Studies Investigating the Antioxidant Activities of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	References
Antioxidant activity in lard	Glycycoumarin	1 g of mixed lard	In vitro	No significant activity	⁹³
Scavenging activity	Glycycoumarin	RAW 264.7 murine macrophages	In vitro	Exerts protective effects by chelating metals or altering iron redox chemistry	¹⁰¹

Antiviral Activities

Many coumarin compounds such as dicamphanoyl-khellactone and calanolide A have been reported to exhibit anti-human immunodeficiency virus (HIV) effects^102,103 via unique mechanisms dependent on the different stages of HIV replication.

A study published in 1988 revealed the anti-HIV activity of licopyranocoumarin and glycycoumarin. These compounds showed inhibitory activity against giant cell formation at 20 μg/mL without any observable cytotoxicity.⁴⁶ To date, however, there has been no other report of licorice-based coumarins exerting this effect. Nonetheless, glycycoumarin was reported to possess activity against the hepatitis C virus (HCV),¹⁰⁴ with a half-maximal effective concentration of 15.5 ± 0.8 mg/mL. In addition, a subsequent report revealed that glycycoumarin, glycyrin, and glycyrol are anti-HCV constituents, with IC₅₀ values of 8.8, 7.2, and 4.6 mg/mL, respectively.¹⁰⁵

Neuraminidase (NA) is an enzyme involved in the release of progeny virus from infected cells and is known to cleave sugars that bind to mature viral particles.¹⁰⁶ Glycyrol, which has a 5-membered closed B ring, demonstrated high (IC₅₀ = 3.1 μM) activity against NA.¹⁰⁷

The specific mechanisms underlying the antiviral activities of these coumarin compounds are shown in Table 11.

Table 11

Summary of Studies Investigating the Antiviral Activity of Coumarin Compounds From Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	References
Anti-HIV activity	Licopyranocoumarin; glycycoumarin	Human lymphoblastic leukemia cell line; OKM-3T	In vitro	Not determined	⁴⁶
Inhibition of hepatitis C viral replication	Glycycoumarin	Human hepatoma cell line; Huh7	In vitro	Decreased translation of the HCV nonstructural protein, NS5A, from the HCV replicon	¹⁰⁴
Anti-HCV	Glycycoumarin; glycyrol; glycyrin	Huh 7.5 cells	In vitro	Inhibition of HCV ribonucleic acid replication and HCV protein synthesis to produce HCV infectious particles	¹⁰⁵
Inhibition of neuraminidase activity	Glycyrol	rvH1N1 (A/Bervig_Mission/1/18) neuraminidase	In vitro	A 5-membered ring between C-4 and C-20 in coumestan is critical for neuraminidase inhibition	¹⁰⁷

Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus.

Antiplatelet and Antithrombotic Activities

Through in vitro experiments, licopyranocoumarin was found to inhibit progressively the aggregation of platelets induced by 0.01 U/mL of thrombin. Furthermore, licopyranocoumarin can suppress the phosphorylation of 40 and 20 kDa proteins, production of inositol 1,4,5-trisphosphate, increase intracellular calcium ions, and activity of phosphodiesterase in platelets.⁴⁷ Thrombin serves as a potent platelet agonist in thrombogenesis.¹⁰⁸ Isotrifoliol is reported to significantly prolong thrombin time (TT) with a good dose-effect relationship (dosage = 2.5 μg/mL, TT prolongation = 10.35 ± 2.38%).⁵¹

The specific mechanisms underlying these activities of coumarin compounds are shown in Table 12.

Table 12

Summary of Studies Investigating the Anticoagulative Activities of Coumarin Compounds in Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	References
Antiplatelet activity	Licopyranocoumarin	Blood obtained from healthy volunteers	In vitro	Inhibition of platelet aggregation by increased intracellular cyclic adenosine monophosphate concentration	⁴⁷
Antithrombotic activity	Isotrifoliol	Blood obtained from rabbits’ common carotid artery	In vitro	-	⁵¹

“-” Denotes not determined.

Other Activities

The specific mechanisms underlying other activities of coumarin compounds are described below and summarized in Table 13.

Table 13

Summary of Studies Investigating Other Activities of Coumarin Compounds in Licorice.

Property	Coumarin compound	Experimental subject	Experimental mode	Mechanism of action	Reference
Estrogenic activity	Glycycoumarin	MCF-7 cells	In vitro	Binds with approximately equal affinity to ERα and ERβ (beta/alpha ratio, approximately 1); increased expression of PgR and GREB1	¹⁰⁹
Acute lung injury	Glycyrol	Human type II alveolar adenocarcinoma basal epithelial, A549 cells; HepG2 cells; KM mice	In vitro; in vivo	Increased levels of CYP3A4, Nrf2, and its downstream detoxification genes GR, GPX, and NQO1	¹¹⁰
Selective probe	Isoglycycoumarin	Human CYP2A6 cells; recombinant CYP2A6; human liver microsomes	In vitro	Cyclize isoprenyl group of isoglycycoumarin entering the active cavity of CYP2A6	¹¹¹

Abbreviations: ER, estrogen receptor; GPX, glutathione peroxidase; GR, glutathione reductase; GREB1, growth regulation by estrogen in breast cancer 1; KM, Kun Ming; NQO1, NAD(P)H quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2-related factor 2; PgR, progesterone receptor.

Estrogenic activity

Glycycoumarin is an estrogen agonist that can stimulate the expression of estrogen-regulated genes; however, the potency and efficacy of glycycoumarin in stimulating the expression of such genes are lower than those of methoxychalcone and vestitol.¹⁰⁹

Protecting against acute lung injury

Paraquat (PQ) is one of the most widely used herbicides in developing countries and a highly toxic compound capable of causing acute lung injury.¹¹² Glycyrol has been shown to decrease the accumulation of PQ in vivo in Kun Ming mice (oral bioavailability = 90.8%, drug-likeness >0.1). In addition, glycyrol has been used to inhibit PQ-induced cell death associated with the cytochrome P450 (CYP450) and Nrf2 pathways in vitro.¹¹⁰

Use as a selective probe

CYP2A6 is an important hepatic phase I detoxifying enzyme¹¹³ with a polymorphism that may be related to smoking and hepatomas.¹¹⁴ Coumarin compounds have been used as probe substrates for CYP2A6 and are subsequently metabolized to 7-hydroxycoumarin.¹¹⁵ CYP2A6 was identified as the major enzyme involved in the metabolism of isoglycycoumarin,¹¹¹ and the catalytic activity of CYP2A6 can be determined by its hydroxylation of isoglycycoumarin to generate licopyranocoumarin.

Discussion

Licorice has been used since ancient times as a common medicinal ingredient and is favored owing to its beneficial activities in the treatment of numerous diseases.^116
-118 To date, the chemistry and pharmacology of licorice have been investigated in many studies in different countries. Although the content of coumarin compounds in licorice is relatively low, an increasing number of researchers are now focusing on their pharmacological activities.

The studies discussed herein have investigated the activities of some coumarin compounds present in licorice such as glycycoumarin, isoglycycoumarin, glycyrol, glycyrin, licopyranocoumarin, licoarylcoumarin, glycyrurol, and Gu-7. These compounds have been reported to exhibit anticancer, hepatoprotective, antispasmodic, immunosuppressive, anti-inflammatory, and antimicrobial activities, as well as therapeutic effects on metabolic syndrome components.

In recent years, natural and synthetic coumarin derivatives have drawn significant attention owing to their potential therapeutic applications in cancer, hepatic disease, and viral infections. In my opinion, coumarins in licorice are mainly indicated for administration to patients with cancer and hepatic disease. Glycycoumarin and glycyrol have been identified as anticancer compounds, where the p53 pathway is activated to induce apoptosis in cancer cells. Glycycoumarin has been reported to be a hepatoprotective compound through the activation of the Nrf2 antioxidant system, stimulation of adenosine monophosphate-activated protein kinase-mediated energy homeostasis, induction of autophagic degradation, and inhibition of the oncogenic kinase T-LAK cell-originated protein kinase. Further studies are required to determine the potential for glycycoumarin and glycyrol as lead molecules for the treatment of cancer and hepatic disease. While some studies have confirmed that glycycoumarin, glycyrol, and glycyrin possess antimicrobial activity, the results are inconsistent.

While performing this literature review, in some cases, the structure presented as glycyrol was found to be neoglycyrol,^{58,59,86

-89} as shown in Figure 2. Glycyrol and neoglycyrol are isomers; glycyrol contains 5′-hydroxy and 7′-methoxy in its structure, whereas neoglycyrol is the converse. Therefore, the structure of glycyrol in those studies should be verified. Additionally, further studies are needed to confirm whether neoglycyrol exerts similar pharmacological effects as glycyrol. Since isoglycycoumarin and glycycoumarin are isomers, they may display similar pharmacological effects, which warrant further study.

Figure 2

Structure of neoglycyrol in licorice.

Similarly, isotrifoliol was misidentified as glycycoumarin in 2 studies.^119,120 Its structure is shown in Figure 1. The structures of these 2 compounds are different; glycycoumarin is chemically 3-arylcoumarin, while isotrifoliol is a coumestan. Isotrifoliol has shown significant antithrombotic activity, but the mechanisms underlying this activity were not elucidated. Another study showed that isotrifoliol isolated from soy leaves exhibits anti-inflammatory effects, specifically inhibiting lipopolysaccharide (LPS)-induced NF-κB and mitogen-activated protein kinase activation by attenuating Toll-like receptor (TLR) signaling in macrophages.¹²¹ Since both licorice and soy belong to the Leguminosae family, it could be inferred that isotrifoliol is present in many plants belonging to this family. Therefore, isotrifoliol could be extracted from more plants from the Leguminosae family for future pharmacological and mechanistic research.

To summarize the present review, glycycoumarin, glycyrol, and glycyrin have been utilized for their anticancer, hepatoprotective, antispasmodic, and antibacterial properties; however, further studies are required to understand their antibacterial mechanism(s) of action. I anticipate that these future studies will contribute to the development and utilization of licorice resources.

Footnotes

Acknowledgments

I would like to express my gratitude to all those who assisted in the preparation of this review. My deepest gratitude goes first to Professor Chunsheng Liu, my supervisor during my Master’s degree, who helped me to identify this review topic. Second, I would like to express my heartfelt gratitude to the Biomedicine College of Beijing City University for providing the resources to complete this review. Finally, I would like to thank “Editage” for their excellent assistance in language editing.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Yimei Zang

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Pharmacological Activities of Coumarin Compounds in Licorice: A Review

Abstract

Keywords

Introduction

Anticancer Activities

Hepatoprotective Activities

Antispasmodic Activities

Therapeutic Activities Toward Metabolic Syndrome

Immunosuppressive and Anti-Inflammatory Activities

Neuroprotective Activities

Antimicrobial Activities

Antioxidant Activities

Antiviral Activities

Antiplatelet and Antithrombotic Activities

Other Activities

Estrogenic activity

Protecting against acute lung injury

Use as a selective probe

Discussion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

ORCID iD

References