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A review of the bioactivity and potential health benefits of licorice Tzu-Chien Kao, Chi-Hao Wu, and Gow-Chin Yen J. Agric. Food Chem., Just Accepted Manuscript • Publication Date (Web): 30 Dec 2013 Downloaded from http://pubs.acs.org on January 5, 2014

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Journal of Agricultural and Food Chemistry

1 2

A review of the bioactivity and potential health benefits of licorice

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Tzu-Chien Kao1, Chi-Hao Wu3, and Gow-Chin Yen1,2*

5 6

1

250 Kuokuang Road, Taichung 402, Taiwan

7 8

2

11

Agricultural Biotechnology Center, National Chung Hsing University, 250 Kuokuang Road, Taichung 40227, Taiwan

9 10

Department of Food Science and Biotechnology, National Chung Hsing University,

3

School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan

12 13

*Author to whom correspondence should be addressed.

14

Tel: 886-4-2287-9755, Fax: 886-4-2285-4378, E-Mail: [email protected]

15 16 17

Running title:

New applications of licorice

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Keywords: Licorice, glycyrrhizic acid, 18β-glycyrrhetinic acid, biological function,

20

safety

21 22

1

ACS Paragon Plus Environment


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Abstract

2 3

Licorice is an herbal plant named for its unique sweet flavor.

It is widely used in the

4

food and tobacco industries as a sweetener. Licorice is also used in traditional

5

Chinese medicine (TCM) and complementary medicine.

6

has long been a part of TCM, the details of its therapeutic applications have been

7

thoroughly established.

8

range of applications. Extracts of and compounds isolated from licorice have been

9

well studied and biologically characterized.

Because the use of licorice

In modern science, licorice is of interest because of its broad

In this review, we discuss the

10

nutraceutical and functional activities of licorice as well as those of the extracts of and

11

the isolated compounds from licorice, including agents with anti-inflammatory

12

activity, cell-protective abilities and chemopreventive effects.

13

licorice are also enumerated.

14

modern science and TCM is also presented, revealing the correspondence of certain

15

characteristics.

The side effects of

A comparison of the activities of licorice described by

16

2


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1

Introduction

2 Licorice, also called liquorice, is the root or stem of Glycyrrhiza glabra (G.

3 4

glabra), which has a sweet flavor.

5

ancient Greek physician Pedanius Dioscorides named licorice γλυκύρριζα

6

(glukurrhiza), meaning “sweet root”; the first part of the word, “γλυκύς”, (glukus)

7

means “sweet”, and the last part of the word “ῥίζα” (rhiza) means “root” (Perseus

8

digital library, http://www.perseus.tufts.edu/hopper/).

9

licorice, Glycyrrhiza glabra (G. glabra), Glycyrrhiza uralensis Fisch. (G. uralensis),

10

In China, licorice is called “gan cao”.

The

Three plants are identified as

and Glycyrrhiza inflata Bat. (G. inflata). Because of its sweet favor, licorice is used in a number of foods, most

11 12

prominently condiments and confectionery.

Condiments such as soy sauce and

13

sweet chili sauce contain licorice powder to add a unique sweet flavor that might be

14

referred to as mellow in English.

15

of the licorice plant is also called licorice.

16

drops are flavored with licorice.

17

of licorice in their products.

Licorice block, powder, and extract can be used in

18

tobacco for multiple purposes.

According to Carmines et al. (1), licorice is added to

19

tobacco to enhance and harmonize the smoke flavor, reduce dryness in the mouth and

20

throat, improve the moisture-holding characteristics of the tobacco to increase its

21

stability and shelf life, act as a surface-active agent during the spraying process of the

22

casing ingredients, improve the uniformity of the absorption of flavors, and minimize

23

the rough smoke character by balancing the overall flavor profile of the tobacco

24

smoke.

25

2), which indicates that it does not represent a hazard to the public when used at

26

typical levels and in a typical manner.

27

ingredient in cosmetics.

28

2% licorice extract led to a significant improvement in erythema, edema, and pruritus

29

(2).

30

the treatment of post-inflammatory hyperpigmentation, including that caused by

31

chemical peeling and laser therapy (3).

32

first step of the oxidation of tyrosinase (4), making it an effective treatment for

33

melasma (5).

Confectionery flavored with an extract of the roots Candies such as Red Vines® and London

Tobacco manufacturers use a considerable amount

Licorice is generally recognized as safe (GRAS, Report No. 28, Conclusion

Licorice is also a common and useful

In a clinical study, topical treatment with a gel containing

Licorice extracts are also used as skin depigmenting agents and are effective in

Licorice extract inhibits the rate-limiting

Furthermore, licorice extract is very useful in the treatment of 3



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1

aphthous ulcers (6); even the deglycyrrhizinated form of licorice (DLG) has a similar

2

positive effect (7).

3

The application of licorice is not restricted to food, tobacco, and cosmetic use;

4

this plant is also used in medicine.

Licorice is considered to be an herbal remedy for

5

many disorders.

6

licorice, including the treatment of wounds, diabetes, cough, and tuberculosis.

7

traditional Chinese medicine (TCM), licorice is one of the most frequently used herbs.

8

Licorice is commonly used in herbal formulae to harmonize other ingredients and to

9

carry the formula to the twelve regular meridians in TCM (9).

Nassiri et al. (8) characterized some of the traditional uses of In

The compendium of

10

Materia Medica (Bencao Gangmu) states that licorice can act as an effective antidote,

11

a detoxicant, a beneficial agent in the development of bone and muscle, and a remedy

12

for throat disorders and cough (9).

13

treating liver disease.

14

disorders (e.g., chronic active hepatitis) (10), although this formula is from Xiao Chai

15

Hu Tang (Minor Bupleurum Formula) in Shang Han Lun of TCM (11).

Licorice is also found in many TCM formulae for

Sho-saiko-to (TJ-9) is frequently used in Japan for liver

16

Modern studies have demonstrated that the uses of licorice in TCM are viable.

17

For example, Ma Huang Tang, a classic Chinese formula composed of Ephedra,

18

Cassia twig, bitter apricot kernel, and prepared licorice, has recently been confirmed

19

to be an effective remedy for pulmonary diseases such as colds, influenza, acute

20

bronchitis, and bronchial asthma.

21

of bitter apricot kernel and prepared licorice on the integral potency of the formula are

22

non-significant.

23

administered with Ephedra or Cassia twigs (12).

24

licorice can harmonize with the other ingredients in the formula, even though it may

25

not be a primary effective ingredient.

26

be an effective method for attenuating both the incidence and severity of

27

postoperative sore throat (13), providing scientific evidence corroborating the

28

TCM-described effect of licorice. Because some of the healing effects described in

29

TCM have been confirmed by modern medicine, an important question arises: which

30

compound(s) in licorice mediate these effects?

The He group demonstrated that the direct effects

However, these two drugs have a significant synergetic effect when That study provides evidence that

A gargle containing licorice has been shown to

31 32

The bioactive compounds in licorice and their biological functions

33

Glycyrrhizic acid and 18β-glycyrrhetinic acid 4


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The sweetness of licorice is derived from glycyrrhizic acid, also called

1 2

glycyrrhizin (Figure 1A).

3

is 30 to 50 times as sweet as sucrose because glycyrrhizic acid can induce impulses

4

from sugar receptor-containing cells at a concentration (3.0 mM) that is much lower

5

than that of sucrose (14).

6

glycyrrhizin maintains its sweetness after heating.

7

taste sweet, but glycyrrhizic acid induces a lower onset sweet flavor than sugar, and

8

its sweetness remains in the mouth for a longer period of time.

9

(18α-glycyrrhetinic acid and 18β-glycyrrhetinic acid) is another triterpenoid in

10

licorice (Figure 1A). Glycyrrhetinic acid can be obtained from the hydrolysis of

11

glycyrrhizic acid.

12

intestinal bacteria that perform glycolysis (15).

13

metabolize glycyrrhizic acid through the action of the glucuronidases of Bacteroides

14

J-37 and Eubacterium sp. to yield 18β-glycyrrhetinic acid (18βGA) (16). Processing

15

(Chinese materia medica) licorice by dry-roasting or honey-roasting (18) to obtain

16

licorice preparata accelerates the hydrolysis of the sugar chains in the saponin and

17

glycosidic flavonoid constituents (17).

18

important agents in TCM, and each has a different function. Recent studies indicate

19

that the anti-inflammatory activities (19) and neuroprotective effects (20) of roasted

20

licorice may be more potent than those of raw licorice, in contrast to the

21

characteristics described by TCM.

22

used to treat the syndrome known as inflammation in modern medicine (Xie Huo in

23

Chinese), and roasted licorice can be used for reinforcement (Bu Zhong in Chinese)

24

(9).

25

licorice, which suggests that glycyrrhizic acid and 18β-glycyrrhetinic acid may have

26

distinct biological properties.

Glycyrrhizic acid is a triterpenoid saponin glycoside and

Furthermore, unlike the sugar substitute aspartame, Both sugar and glycyrrhizic acid

Glycyrrhetinic acid

This process can be completed by presystemic metabolism by Human intestinal bacteria

Raw licorice and licorice preparata are both

Bencao Gangmu suggests that raw licorice can be

For example, roasted licorice is used in Buzhong Yiqi Tang instead of raw

27

Because licorice has been used alone and as a component in many formulas to

28

treat liver diseases, multiple mechanisms have been proposed for the hepatoprotective

29

effects of glycyrrhizic acid and 18β-glycyrrhetinic acid.

30

18β-glycyrrhetinic acid can protect rat hepatocytes from bile acid-induced

31

cytotoxicity (21).

32

demonstrated; the intravenous administration of glycyrrhizic acid decreases serum

33

ALT and necro-inflammation and fibrosis in the liver (22).

Both glycyrrhizic acid and

Recently, a beneficial effect of glycyrrhizic acid on hepatitis was

5


Many mechanisms are


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1

involved in the protective effects of glycyrrhizic acid and 18β-glycyrrhetinic acid.

2

These mechanisms likely involve reduced AST (aspartate transaminase, also called

3

GOT) and ALT (alanine transaminase, also called GPT) activities.

4

receptor (PXR), as well as the cytochrome P450 family 3 subfamily A (CYP3A), can

5

also be modulated by glycyrrhizic acid to protect against lithocholic acid-induced

6

injury (23).

7

inhibit liver fibrosis (24), which may lead to cancer.

8 9

The pregnane X

Both glycyrrhizic acid and 18β-glycyrrhetinic acid treatments can

In addition to liver protection, glycyrrhizic acid and 18β-glycyrrhetinic acid may be effective in the protection of other organs.

Both glycyrrhizic acid and

10

18β-glycyrrhetinic acid have positive effects on brain damage induced by

11

ischemia and 6-hydroxydopamine (25).

12

glycyrrhizic acid and 18β-glycyrrhetinic acid can penetrate the blood-brain barrier

13

(BBB)

14

18β-glycyrrhetinic acid are potent agents for the treatment of neural diseases,

15

ischemic brain diseases and Parkinson’s disease.

16

protective effects in the kidney; studies have demonstrated that glycyrrhizic acid

17

protects against cisplatin-induced genotoxicity and nephrotoxicity (27).

18

effects have also been observed with a renal hypoxia-reoxygenation model.

19

However, 18β-glycyrrhetinic acid does not exhibit the same potential (28).

20

Glycyrrhizic acid seems to be effective against ischemic damage, including damage to

21

the spinal cord (28), myocardium (29), liver (30) and gut (31).

22

(26).

These

findings

A recently study demonstrated that

indicate

that

glycyrrhizic

acid

and

Glycyrrhizic acid also exhibits

Protective

Glycyrrhizic acid and 18β-glycyrrhetinic acid are considered inhibitors of

23

inflammation induced by both bacterial and viral infection.

Because inflammation is

24

frequently triggered by bacteria or viral infection, anti-bacterial and anti-viral

25

activities are possible anti-inflammatory strategies.

26

replication of and infection by various viruses (32), including SARS (severe acute

27

respiratory syndrome)-associated coronavirus (33), HIV (human immunodeficiency

28

virus) (34), hepatitis A virus (HAV) (35), hepatitis B virus (HBV) (36), hepatitis C

29

virus (HCV) (37), herpesviridae (varicella zoster virus, VZV) (38), herpes simplex

30

virus 1 (HSV-1) (39), Epstein-Barr virus (EBV) (40), cytomegalovirus (CMV) (41),

31

and influenza viruses, including H1N1 (42) and H5N1 (43).

32

that glycyrrhizic acid inhibits the growth of Helicobacter pylori, and thus, this agent

33

can be used in the treatment of gastric ulcers (44).

Glycyrrhizic acid can inhibit the

Studies also indicate

18βGA has also been shown to be

6


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1

effective against clarithromycin-resistant strains of Helicobacter pylori (45).

Further

2

studies have revealed that glycyrrhizic acid and 18β-glycyrrhetinic acid can modulate

3

inflammation-related mechanisms.

4

effect of other formulas that act as anti-inflammatory agents.

5

enhances the anti-inflammatory effect of licorice extract without glycyrrhizic acid

6

(46).

7

H5N1-induced pro-inflammatory gene expression without affecting the cytolytic

8

activity of natural killer cells.

9

modulate inflammation by two methods of regulation, the inhibition of

TCM often incorporates licorice to enhance the Glycyrrhizic acid

Michaelis et al. (43) also demonstrated that glycyrrhizic acid can inhibit

These results indicate that glycyrrhizic acid might

10

proinflammatory cytokines and the promotion of immune function.

11

role in this regulation.

12

inflammation very effectively, and glucocorticoids (e.g., dexamethasone) are used

13

extensively in clinical treatment.

14

involvement of glycyrrhizic acid and 18β-glycyrrhetinic acid in the induction of

15

cortisone activity.

16

glucocorticoid receptor (GR) signaling by binding to the GR (47) and inhibiting the

17

activity of corticosteroid 11β-dehydrogenase isozyme 2 (11β-HSD2), which converts

18

active cortisol into inactive cortisone (48, 49).

19

18β-glycyrrhetinic acid may also enhance GR signaling by eliminating intracellular

20

oxidative stress (50).

21

it does not seem to increase glucocorticoid-induced side effects.

22

excessive glucocorticoid levels exert diverse effects on bone microstructure, integrity,

23

and mineral metabolism (51).

24

has the potential to be used as an agent to protect bone against glucocorticoid-induced

25

osteoporosis.

26

functions extracellularly as a signaling molecule in acute and chronic inflammation, is

27

inhibited by binding to glycyrrhizic acid (53).

28

18β-glycyrrhetinic acid can modulate PI3K signaling to alleviate inflammation

29

(Figure 2) (50).

30

18β-glycyrrhetinic acid have considerable potential for development as novel

31

inflammation-modulating agents.

32 33

PI3K may play a

Glucocorticoids and the glucocorticoid receptor modulate

There are several potential mechanisms for the

Glycyrrhizic acid and 18β-glycyrrhetinic acid can activate

Glycyrrhizic acid and

Although glycyrrhizic acid can enhance glucocorticoid activity, For example,

Ramli et al. (52) demonstrated that glycyrrhizic acid

High-mobility group box 1 (HMGB1), a nuclear component that

Glycyrrhizic acid and

Altogether, these results suggest that glycyrrhizic acid and

Glycyrrhizic acid and 18β-glycyrrhetinic acid also affect the biological mechanism of cancer formation.

Glycyrrhizic acid may inhibit angiogenesis by 7



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1

targeting ERK signaling (54).

Glycyrrhizic acid also protects against UVB-induced

2

carcinogenesis in the epidermis of SKH-1 hairless mice (55).

3

effective against HCV-induced liver disorders, it also prevents hepatocarcinogenesis

4

associated with hepatitis (56, 57).

5

anti-carcinogenesis effect than glycyrrhizic acid.

6

induces apoptotic cell death but also exhibits a synergistic toxic effect with antibiotics

7

and anti-cancer drugs (e.g., camptothecin, mitomycin c, and doxorubicin) (58).

8

Glycyrrhetinic acid, oleanolic acid, and ursolic acid have similar chemical structures

9

and potent anti-ulcer activities (59).

Because GA is

Glycyrrhetinic acid has a more potent 18β-Glycyrrhetinic acid not only

Compounds whose chemical structures are

10

similar to that of glycyrrhetinic acid also provide a satisfactory anti-carcinogenesis

11

outcome (60).

12

and its derivatives, including the human epithelial ovarian carcinoma cell lines

13

OVCAR-3 and SK-OV-3 (61, 62), the human prostate cancer cell lines DU145 (63, 64)

14

and PC3, the human breast cancer cell line MCF7 (65, 66), the human bladder cancer

15

cell line NTUB1 (67), the human leukemia cell line HL60 (68), the human

16

erythromyeloblastoid leukemia cell line K562 (69), the human colon cancer cell lines

17

RKO and SW480 (70), the pancreatic cancer cell lines Panc1 and Panc28 (71), and

18

many other cell lines. 18β-Glycyrrhetinic acid is more toxic than glycyrrhizic acid;

19

glycyrrhizic acid displays no obvious cell toxicity, even at 200 µM (25, 47, 50).

Many cancer cells are sensitive to treatment with glycyrrhetinic acid

20

Glycyrrhizic acid and glycyrrhetinic acid can bind to DNA (72) and RNA (73).

21

This behavior implies that glycyrrhizic acid and glycyrrhetinic acid may directly

22

interfere with the pattern of transcription factors, the targeting of gene expression, and

23

the interactions of DNA and RNA.

24

for understanding the biological functions of glycyrrhizic acid and glycyrrhetinic acid.

25

Based on the above evidence, glycyrrhizic acid and 18β-glycyrrhetinic acid have

26

distinct biological functions, which may be due to the differences in their chemical

27

structures.

This issue might be a promising research topic

28 29

Liquiritin, Isoliquiritin, Liquiritigenin, and Isoliquiritigenin

30

Liquiritigenin and isoliquiritigenin are chalconoids of licorice; liquiritin and

31

isoliquiritin are the glycone forms of liquiritigenin and isoliquiritigenin, respectively

32

(Figure 3A).

33

liquiritigenin, and isoliquiritigenin are limited, these compounds are considered to be

Although studies of the antioxidant abilities of liquiritin, isoliquiritin,

8


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1

potent protective agents against cancer.

These four compounds may have a potent

2

antispasmodic effect (74).

3

TCM formula that is used to achieve tussive relief.

4

four compounds play an important role in licorice’s healing effects (75).

5

the chemical structures of these compounds are similar, the simultaneous study of all

6

four compounds may facilitate the elucidation of the relationship between their

7

biological effects and structure.

Mai Men Dong Tang is a widely used licorice-containing Researchers believe that these Because

8

The biological functions of liquiritin are similar to those of glycyrrhizic acid.

9

Liquiritin promotes neurite outgrowth in PC12 cells with nerve growth factor

10

treatment (76), suggesting its potential as a remedy for neurodegenerative diseases

11

such as Alzheimer's disease or Parkinson's disease.

12

exhibit an antidepressant-like effect in chronic variable stress-induced depression

13

model rats by modulating oxidative stress (77).

14

induction of the RAGE/NFκB pathway in human umbilical vein endothelial cells

15

(HUVECs) by advanced glycation end products (AGE), which may benefit patients

16

with diabetes mellitus (78).

17

immune responses (79), enhance antioxidant enzymes such as SOD, catalase, and

18

glutathione peroxidase in mice focal cerebrum (80), and might act as protective agents

19

against epithelial injury in chronic obstructive pulmonary disease (COPD) (81).

20

with glycyrrhizic acid, liquiritin may bind to DNA (82).

21

affect gene expression or other DNA-related mechanisms.

22

glycyrrhizic acid are glycones or glycosides, functional groups that may be important

23

for DNA binding, although this characterization has yet to be confirmed.

24

Furthermore, liquiritin may

Liquiritin also attenuates the

Liquiritin and glycyrrhizic acid can also stimulate

As

Liquiritin may directly Both liquiritin and

There are few studies of isoliquiritin listed in the PubMed database, and most are

25

concerned with its isolation and identification.

26

angiogenesis and tube formation in granulomas (83) and may also have a potent

27

antitussive effect (84).

28

depigmentation due to tyrosinase inhibition (85).

29

limited because of its lack of commercial availability.

30

Isoliquiritin is thought to prevent

Another possible application of isoliquiritin is skin Research on isoliquiritin may be

Liquiritigenin is a well-known selective estrogen receptor β agonist (86) that has

31

been implicated in the weight-reducing effects of licorice oil (87).

32

may facilitate the recovery of learning and memory deficits induced by amyloid beta

33

Aβ(25-35) (88) and also help to enhance osteoblast function (89). 9


Liquiritigenin

Both


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1

liquiritigenin and isoliquiritigenin are able to inhibit xanthine oxidase (90), a

2

promoting factor in many disorders.

3

49.3 µM for liquiritigenin and 55.8 µM for isoliquiritigenin.

4

isoliquiritigenin display potential PPARγ activating activity (91), suggesting their

5

potential for use in recovery from metabolic syndrome.

6

inhibitor of aldose reductase, which suggests that it might be effective in treating

7

diabetic complications (92).

8

effective

9

proinflammatory cytokines by blocking NFκB (93), while isoliquiritigenin can

10

influence the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell

11

adhesion molecule-1 (VCAM-1) to modulate inflammation (94).

12

organs, liquiritigenin has a protective role against a number of injuries, including

13

acetaminophen-induced rat liver damage (95), cadmium-induced rat hepatoma Reuber

14

H35 cell (H4IIE) damage (96), d-galactosamine/lipopolysaccharide- or CCl4-mediated

15

rat hepatitis (97), Aβ(25-35)-induced injury of rat hippocampal neurons (98), and

16

infection by Candida albicans (99).

17

organs by inhibiting cisplatin-induced rat anorexia (100), the hyperaggregability of

18

platelets induced by diabetes (101), and the accumulation of cyclic AMP in rat

19

ventricular heart muscle (102) and by potently promoting neuronal health by

20

inhibiting monoamine oxidase A and B (103), among other mechanisms.

21

liquiritigenin can enhance bile secretion via a choleretic effect and can enhance the

22

activity of transporters and phase II enzymes in the liver (104).

23

thought to be related to the antidote ability of licorice.

24

secretion, liquiritigenin might increase the rate of hepatic blood flow (105).

25

Liquiritigenin may also exhibit chemopreventive activity in liver cancer (106, 107)

26

and lung cancer (108).

27

chemoprevention might involve apoptotic molecular targets, such as cytochrome c,

28

caspases (109), matrix metalloproteinases (MMPs), PI3K, Akt (110), and

29

vascularization (111).

30

may enhance the induction of H4IIE and C6 glioma cell apoptosis without affecting

31

its antioxidative properties (112).

32

lipoxygenase and prostaglandin E2 (PEG2) (113), induce cell cycle arrest in the

33

human prostate cancer cell lines DU145 and LNCaP cells (114), induce cell death in

The IC50 values of these compounds are similar, Both liquiritigenin and

Isoliquiritigenin is also an

In addition, both liquiritigenin and isoliquiritigenin are

anti-inflammatory

agents.

Liquiritigenin

inhibits

iNOS

and

In many cells and

Isoliquiritigenin also protects many cells and

In the liver,

This effect is

In addition to increasing bile

The mechanisms by which liquiritigenin modulates

Notably, C8-prenylation of a flavonoid such as liquiritigenin

Isoliquiritigenin has been reported to inhibit

10


Page 11 of 36


1

the human breast cancer cell line MCF7 at high concentration (115), suppress

2

pulmonary metastasis of mouse renal cell carcinoma (116), inhibit human lung cancer

3

cell growth (117), inhibit colon cancer in ddY mice (118, 119), induce apoptosis in

4

human MGC803 gastric cancer cells (120), and activate the apoptosis in hepatoma

5

cells (121, 122) among other effects in cancer cell.

6

protectant in cells and organs, whereas isoliquiritigenin exhibits greater potential in

7

cancer chemoprevention.

8 9

Thus, liquiritigenin is a potent

Liquiritigenin and isoliquiritigenin have also been applied in the treatment of cocaine addiction.

Although the results are preliminary, liquiritigenin improved the

10

selective molecular and behavioral disorders associated with cocaine use (123), and

11

isoliquiritigenin inhibited the dopamine release induced by cocaine (124).

12

research has high practical value and is worth further study.

This

13 14

Dehydroglyasperin C and Dehydroglyasperin D

15

Dehydroglyasperin is an isoflavonoid isolated from licorice that has two

16

isoforms, dehydroglyasperin C (DGC) and dehydroglyasperin D (DGD) (Figure 3B)

17

(125).

18

antioxidants, although the potency of DGC is greater.

19

isoangustone A, was identified by Lee et al. (125).

20

isoangustone A is lower than that of DGD (126).

21

DGC and DGD are also classified as phenylflavonoids (126) and are strong Another phenylflavonoid, The antioxidant activity of

DGC and DGD are potent ligands of peroxisome proliferator-activated receptor γ

22

(PPARγ), which is thought to play a role in metabolic syndrome.

Treatment with an

23

ethanolic extract of licorice containing DGC and DGD prevents and ameliorates

24

metabolic syndrome in diabetic KK-Ay and obese C57BL mice (127).

25

only a ligand of PPARγ but also an activating factor of Nrf2 and detoxifying enzymes

26

(128).

27

glutamate-induced neuronal cell damage (129).

28

various potent activities, they are relatively newly isolated compounds in licorice, and

29

further study of their biology and toxicity is needed.

DGC is not

PI3K/Akt and Nrf2-Keap1 are also modulated by DGC to protect against While DGC and DGD exhibit

30 31 32 33

Glabridin Glabridin (Figure 3B) is a licorice isoflavonoid with antimicrobial (130) and antioxidant properties (131).

Because of its well-described antioxidant capabilities, 11



Page 12 of 36

1

glabridin is frequently used in studies of oxidative stress, including LDL oxidation

2

(132).

3

shown that glabridin might modulate bone disorders in post-menopausal women (133)

4

and increases in osteoblastic cell function (134).

5

antioxidant, brain penetration of glabridin through the BBB is altered by

6

P-glycoprotein, which might limit the application of glabridin in central nervous

7

system (CNS) diseases (135).

8

The structure of glabridin is similar to that of estradiol-17β, and studies have

Although glabridin is a potent

The main application of glabridin might be cosmetics.

The antioxidant ability

9

of glabridin might help modulate anti-inflammatory mechanisms in skin tissue.

10

Although clinical studies are lacking, some commercial formulations contain licorice

11

extract and claim that glabridin is useful for skin depigmentation (136).

12

and its derivatives (137) inhibit tyrosinase, and there have been reports of a reduction

13

in UVB-induced pigmentation and erythema in brownish guinea pigs when glabridin

14

was administered for three weeks after UVB irradiation (138).

15

anti-inflammatory activity, glabridin can inhibit inducible nitric oxide synthase (iNOS)

16

expression (139) and upregulate manganese superoxide dismutase (SOD), catalase,

17

and paraoxonase 2 expression (140).

18

Glabridin

As part of its potent

Increasing evidence indicates that glabridin may be beneficial in the treatment of

19

diabetes mellitus and related diseases.

Licorice flavonoid oil (LFO, also called

20

Kaneka Glavonoid Rich Oil) contains glabridin as the bioactive flavonoid and

21

suppresses abdominal fat accumulation and blood glucose levels in KK-Ay mice (141).

22

LFO can activate AMP-activated protein kinase (AMPK) and ameliorate the increases

23

in fatty liver and in the triglyceride and cholesterol plasma levels induced by obesity

24

(142).

LFO administered daily up to 1200 mg/day is considering safe in humans

25

(143).

Based on this finding, LFO might be safe as a functional food.

26

also works as a cancer preventive agent.

27

non-small cell lung cancer A549 cells and inhibits the migration, invasion, and

28

angiogenesis of A549 cells (144).

29

cosmetics should be explored.

Glabridin

It blocks FAK/rho signaling in human

Based on these studies, uses of glabridin beyond

30 31 32 33

Carbenoxolone Sodium

carbenoxolone

(also

called

carbenoxolone

or

CBX)

is

the

3-hemisuccinate of glycyrrhetinic acid and may be the best-known derivative of 12


Page 13 of 36


1

glycyrrhetinic acid (Figure 1B).

2

carbenoxolone is freely soluble in water (145).

3

carbenoxolone is similar to that of glucocorticoids, and CBX can be used as an

4

anti-inflammatory agent and an inhibitor of 11β-hydroxysteroid dehydrogenase type 1

5

(146).

6

related to its effectiveness in the prevention of fatty liver (147).

7

regulatory ability of glucocorticoids, carbenoxolone might have a nootropic effect by

8

improving verbal fluency and verbal memory in humans (148).

9

Gangmu has been quoted as stating that licorice consumption may enhance memory.

10

The best-known modern application of carbenoxolone is gastric ulcer treatment,

11

which is based on the spironolactone (149) and has good outcome in aphthous ulcers

12

(150).

13

As the disodium salt of the 3-o-hydrogen succinate, The chemical structure of

Sterol regulation is a very important characteristic of carbenoxolone, which is Because of the

In TCM, Bencao

Carbenoxolone is also a well-known gap junction inhibitor and is widely used in

14

neuroscience research (151).

Gap junctions are also important in glutamate-induced

15

neurotoxicity, and carbenoxolone can decrease the toxic effects of glutamate (152).

16

Carbenoxolone also protects against ischemic injury in skeletal muscle and the

17

hippocampus resulting from gap junction inhibition (153).

18

related to pain control because the spinal cord glia exhibit extensive gap junctional

19

connectivity, which is involved in the contralateral spread of excitation that results in

20

mirror image pain (154).

21

application in pain relief is not unreasonable.

22

and Cx26) initiate brain metastatic lesion formation in association with the

23

vasculature.

24

involvement (155). Carbenoxolone is frequently used in cancer research to probe the

25

relationship between gap junctions and cancer formation, such as in the study of the

26

relationship between gap function and breast cancer metastasis or melanoma brain

27

colonization (155).

28

widely applied in clinical treatments.

Gap junctions are also

Because carbenoxolone is an inhibitor of gap junctions, its Connexin gap junction proteins (Cx43

Carbenoxolone can prevent tumor cell extravasation and blood vessel

Carbenoxolone is a useful agent for many research fields and is

29 30

Safety of Licorice

31 32 33

Although licorice is considered to be a non-toxic herb in TCM, some health concerns may be associated with the use of licorice.

Clinical studies show that

13



Page 14 of 36

1

licorice may cause edema and apparent mineralocorticoid excess syndrome because

2

glycyrrhizic acid and glycyrrhetinic acid can inhibit the activity of 11β-hydroxysteroid

3

dehydrogenase type 2 (11β-HSD2) (48, 49), which converts biologically active

4

cortisol into the inactive compound cortisone, thereby preventing the overstimulation

5

of the mineralocorticoid receptor by cortisol (156).

6

lead to excessive sodium ion levels and the excretion of potassium ions, which may

7

cause water retention and lead to hypertension.

8

with

9

hyperaldosteronism and may lead to hypertension and heart disease (157).

10

Licorice-induced hypertension can be reversed by stopping the intake of

11

licorice-based products (157).

12

inhibited by licorice, and licorice constituents can cause hypertonia and hypokalemia

13

because of the associated change in potassium levels in the blood.

14

are associated with the intake of carbenoxolone because it is a more potent inhibitor

15

of 11βHSD2 (IC50: 20-50 nM) than 11βHSD1 (IC50: 1.8 µM) (49) (Figure 4).

16

Potassium levels are also affected by digoxin (158), which might act synergically with

17

licorice intake.

18

licorice extract, which may reduce glycyrrhizic acid and glycyrrhetinic acid-induced

19

side effects.

licorice

may

cause

low

potassium

Mineralocorticoid overdose can

Excessive daily supplementation levels

due

to

licorice-induced

11β-Hydroxysteroid dehydrogenase type 2 is

Similar concerns

Some products use deglycyrrhizinated licorice (DGL) instead of raw

20

Excessive licorice intake may also influence the effects of other medicine.

21

Glabridin may inhibit human cytochrome P450 (159), an important enzyme in drug

22

metabolism and bioactivation (160).

23

(coumadin), an anticoagulant agent, into its inactive form (161), and thus, licorice

24

may increase warfarin clearance (162).

25

consulting a physician is strongly advised before consuming foods containing licorice.

26

Cytochrome P450 metabolizes warfarin

If treatment with warfarin is required,

Pregnant women should consider limiting their intake of licorice.

Little

27

research has examined the teratogenicity of licorice, but a single study has indicated

28

that licorice may aggravate cyclophosphamide-induced body weight loss and

29

malformations of fetuses by upregulating cytochrome P450 type 2B (163).

30

a study conducted in Korea indicated that women taking licorice for cough and cold

31

control did not have an increased risk of stillbirths (164).

32

estrogen levels in humans (165) and may increase the risk of estrogen-mediated

33

cancer (166).

However,

Licorice also increases

Licorice can potentially cause an anti-androgenic effect (167, 168), 14


Page 15 of 36


1

which may lead to erectile dysfunction.

2

licorice-related food is highly advised.

To avoid these side effects, careful intake of

3 4 5 6

Conclusion Licorice is extensively used in the TCM, and appears as a component herb in

7

about 60% of all TCM prescriptions.

Numerous in vitro and in vivo studies have

8

suggested healthful properties of licorice and its bioactive constituents such as

9

glycyrrhizic acid, 18β-glycyrrhetinic acid, carbenoxolone, dehydroglyasperin C, and

10

dehydroglyasperin D as well as some unique compounds like glabridin, licoricidin,

11

licorisoflavan A, and licochalcone A have potential beneficial effects in human

12

diseases.

13

anti-oxidative, anti-microbial, anti-virus, and antidote properties of the compounds as

14

summarized in Table 1.

15

humans, all of these side effects should be reversible.

With proper control of licorice

16

intake, its health benefits outweigh its side effects.

It is highly recommended that

17

before beginning the regular intake of any food or medicine containing licorice and its

18

related compounds, one should consult a traditional Chinese physician.

19

opinion, licorice and the compounds isolated from this plant can be used as a

20

complement to aid current medicines to reduce/eliminate side effects and improve the

21

healing efficacy and outcome.

These effects have been associated with the anti-inflammatory,

Although licorice intake may have some side effects in

In our

22 23 24

Acknowledgements

25

This research work was supported in part by the National Science Council,

26

NSC99-2628-B005-003-MY3, Taiwan, R.O.C., and by the Ministry of Education,

27

Taiwan, R.O.C. under the ATU plan.

28 29

Conflict of interest statement

30

The authors have declared no conflict of interest.

31 32 33 15



1

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Hoffman, R.; VandenBerg, S. R.; Klemke, R. L., Role of connexins in metastatic breast cancer and melanoma brain colonization. Journal of cell science 2013, 126, 904-13. 156. Hardy, R. S.; Raza, K.; Cooper, M. S., Endogenous glucocorticoids in inflammation: contributions of systemic and local responses. Swiss medical weekly 2012, 142, w13650. 157. Ruiz-Granados, E. S.; Shouls, G.; Sainsbury, C.; Antonios, T., A salty cause of severe hypertension. BMJ case reports 2012, 2012. 158. Bielecka-Dabrowa, A.; Mikhailidis, D. P.; Jones, L.; Rysz, J.; Aronow, W. S.; Banach, M., The meaning of hypokalemia in heart failure. International journal of cardiology 2012, 158, 12-7. 159. Kent, U. M.; Aviram, M.; Rosenblat, M.; Hollenberg, P. F., The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9. Drug metabolism and disposition: the biological fate of chemicals 2002, 30, 709-15. 160. Guengerich, F. P., Cytochrome p450 and chemical toxicology. Chemical research in toxicology 2008, 21, 70-83. 161. Cavallari, L. H.; Limdi, N. A., Warfarin pharmacogenomics. Current opinion in molecular therapeutics 2009, 11, 243-51. 162. Mu, Y.; Zhang, J.; Zhang, S.; Zhou, H. H.; Toma, D.; Ren, S.; Huang, L.; Yaramus, M.; Baum, A.; Venkataramanan, R.; Xie, W., Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J Pharmacol Exp Ther 2006, 316, 1369-77. 163. Park, D.; Yang, Y. H.; Choi, E. K.; Yang, G.; Bae, D. K.; Lee, S. H.; Kim, T. K.; Kyung, J.; Kim, D.; Choi, K. C.; Kim, Y. B., Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA. Birth defects research. Part B, Developmental and reproductive toxicology 2011, 92, 553-9. 164. Choi, J. S.; Han, J. Y.; Ahn, H. K.; Ryu, H. M.; Kim, M. Y.; Chung, J. H.; Nava-Ocampo, A. A.; Koren, G., Fetal and Neonatal Outcomes in Women Reporting Ingestion of Licorice (Glycyrrhiza uralensis) during Pregnancy. Planta Med. 2013, 79, 97-101. 165. Armanini, D.; Fiore, C.; Mattarello, M. J.; Bielenberg, J.; Palermo, M., History of the endocrine effects of licorice. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 2002, 110, 257-61. 166. Boucher, B. A.; Cotterchio, M.; Curca, I. A.; Kreiger, N.; Harris, S. A.; Kirsh, V. A.; Goodwin, P. J., Intake of phytoestrogen foods and supplements among women recently diagnosed with breast cancer in Ontario, Canada. Nutrition and cancer 2012, 64, 695-703. 167. Zamansoltani, F.; Nassiri-Asl, M.; Sarookhani, M. R.; Jahani-Hashemi, H.; Zangivand, A. A., Antiandrogenic activities of Glycyrrhiza glabra in male rats. International journal of andrology 2009, 32, 417-22. 168. Armanini, D.; Bonanni, G.; Mattarello, M. J.; Fiore, C.; Sartorato, P.; Palermo, M., Licorice consumption and serum testosterone in healthy man. Experimental and clinical endocrinology & diabetes; official journal, German Society of Endocrinology [and] German Diabetes Association 2003, 111, 341-3.

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1

Figure legends.

2 3

Figure 1.

4

the derivative of glycyrrhetinic acid, carbenoxolone (B) in licorice.

Chemical structures of glycyrrhizic acid and glycyrrhetinic acid (A) and

5 6

Figure 2.

7

18β-glycyrrhetinic acid.

8

PI3K signaling to upregulate the antioxidant system, leading to reduced intracellular

9

ROS.

10

The proposed anti-inflammatory mechanism of glycyrrhizic acid and Glycyrrhizic acid and 18β-glycyrrhetinic acid can modulate

Therefore, PI3K signaling also enhances GR signaling and modulates

cytokines (47, 50).

11 12

Figure 3.

13

licorice.

Chemical structures of the chalconoids (A) and the isoflavonoids (B) in

14 15

Figure 4.

16

glycyrrhetinic acid, and carbenoxolone.

17

11βHSD1 and 11βHSD2.

18

inactive cortisone, whereas 11βHSD1 converts inactive cortisone into active cortisol.

19

Studies have shown that both glycyrrhizic acid and glycyrrhetinic acid can inhibit

20

11βHSD2, as can carbenoxolone.

21

its derivative, carbenoxolone, may have greater potency than glycyrrhizic acid.

11β-Hydroxysteroid dehydrogenase inhibition caused by glycyrrhizic acid, There are two isoforms in humans,

11βHSD2 converts biologically active cortisol into

For 11βHSD1 inhibition, glycyrrhetinic acid and

22

28


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1 (A)

Glycyrrhetinic acid

Glycyrrhizic acid

(B)

Carbenoxolone

Figure 1.

29



Figure 2.

30


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(A) Chalconoids of licorice

Liquiritin

Isoliquiritin

Liquiritigenin

Isoliquiritigenin

(B) Isoflavonoids of licorice

Dehydroglyasperin C

Dehydroglyasperin D

Figure 3.

31


Glabridin


Figure 4.

32


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Table 1. The in vivo biological functions of compounds in licorice

Biological function

Species

Targeting/mechanism

Reference

Glycyrrhizic acid sugar substitute

hepatoprotection

Phormia regina

human, rat, mice

stimulates pyranose receptor site and furanose receptor site

14

liver necrosis↓, mitochondrial

22, 21, 24,

permeability transition ↓, ROS ↓, cytochrome c ↓, HMGB1 ↓, harboring alpha2(I) collagen

30

gene promoter nephroprotection

mice

antioxidant enzymes ↑

27

renal protection

rat


28

cardio protection

rat


29

gut protection

rat

mean arterial blood pressure ↓, NFκB ↓

31

anti-osteoporosis

rat

11β-HSD1 dehydrogenase ↓

52

HCV-induced hepatocellular

56, 57, 54,

carcinogenesis ↓, ERK ↓, thymine dimer ↓, PCNA ↓, NFκB ↓, p53

55

21, 24

anti-carcinogenesis

human, rat, mice

Glycyrrhetinic acid

hepatoprotection

rat, mice

Caspase 3/10 ↓, PARP ↓, JNK ↓, mitochondrial integrity ↑, ROS ↓, cytochrome c ↓, harboring alpha2(I) collagen gene promoter ↓, Smad3 ↓

anti-ulcer

monkey

gastric PGE2 ↑

59

antispasmodic

rat

muscle contraction ↓

74

antitussive

guinea pig

cough ↓

75

anti-depression

rat


77

promote immune

human

CD69 ↑

79

neuroprotection

mice


80

rat


74

liquiritin

isoliquiritin antispasmodic

33



antitussive

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guinea

cough ↓, ATP-sensitive

pig

potassium channel

hepatoprotection

rat

liver necrosis ↓, mortality ↓, hepatic blood flow rate ↑

95, 105

neuroprotection

rat

behavioral performance ↑, Notch2 ↓

88

antispasmodic

rat


74

antitussive

guinea

cough ↓

75

75, 84

Iiquiritigenin

pig anti-depression

rat

monoamine oxidase A and B ↓

103

anti-cocaine addiction

rat

hyperlocomotion ↓, CREB ↓, c-Fos ↓

123

antidote

rat

transporters activity ↑, phase-II 104 enzymes ↑ 107, 111

mice

tumor growth ↓, apoptosis ↑, microvascular density ↓, VEGF ↓

antispasmodic

rat


74

antitussive

guinea pig

cough ↓

75

anti-diabetes

rat

aldose reductase activity ↓

92

anti-anorexia

rat

5-HT2B antagonist

100

cyclooxygenase activity ↓,

101

anti-carcinogenesis Isoliquiritigenin

lipoxygenase activity ↓, peroxidase activity ↓, acts as aldose reductase inhibitor

anti-platelet

platelet

cardiotonic

rat

cyclic AMP ↑

102

anti-depression

rat, mice

monoamine oxidase A and B ↓

103 113, 116, 118 – 119

mice

PGE2 ↓, platelet 12-lipoxygenase and 5-lipoxygenase ↓, immune ↑, direct cytotoxicity, iNOS ↓,

anti-carcinogenesis

preneoplastic aberrant crypt foci ↓, aberrant crypt focus formation ↓ anti-cocaine

rat

extracellular dopamine level ↓, 34


124

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addiction

GABA(B) receptor modulation

Dehydroglyasperin C/dehydroglyasperin D anti-diabetes

mice

PPARγ ligand, spontaneously hypertension ↓

127

rat

structure similar to estradiol-17β

133

body weight (gain) ↓, abdominal adipose tissues ↓,

141

Glabridin anti-osteoporosis

anti-diabetes

mice

anti-obesity

rat

AMPK ↑

142

depigmentation

guinea pig

T1 and T3 tyrosinases ↓, ROS ↓, COX ↓

138

anti-inflammation

mice

NFκB ↓, ROS ↓

139

blood glucose level ↓, PPARγ ↑

35



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Bioactivity and Potential Health Benefits of Licorice - Journal of

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