Two chemicals from Yashtimadhu-Licorice (Glycyrrhiza glabra)
Two chemicals from
Yashtimadhu-Licorice (Glycyrrhiza glabra)
Dr.
Hemant Vinze M.S.
Introduction
Yashtimadhu-licorice
(Glycyrrhiza glabra) is rich in
pharmacologically active chemicals. In this article I discuss the pharmacology
of Glycyrrhizin and Glycyrrhetinic acid.
Glycyrrhizin
Molecular formula: C42H62O16
Structural formula:
Glycyrrhizin (or glycyrrhizic acid
or glycyrrhizinic acid) is the chief constituent of the root of
Yashtimadhu-licorice (Glycyrrhiza glabra). It is sweet in taste being
30-50 times sweeter than sucrose (cane sugar). It is a triterpenoid-saponin
extracted from the root of the plant and is used as an emulsifier and gel-forming
agent in food stuff and cosmetics. Its aglycone is oxolone. Glycyrrhizine has
therefore been used as a prodrug for that compound. The content of
glycyrrhizin/ glycyrrhizic acid in Yashtimadhu-licorice (Glycyrrhiza
glabra) root is 2-24 % of the dry weight. [1]
Pharmacokinetics of glycyrrhizic
acid
After oral ingestion, glycyrrhizin
is hydrolysed to 18 β-glycyrrhetinic acid by intestinal bacteria. After
absorption from the gut β-glycyrrhetinic acid is metabolized to
3 β-monoglucuronyl-18 β-glycyrrhetinic acid in the liver. The
metabolite then circulates in the blood. Consequently, its oral bioavailability
is poor. The major part is eliminated by bile and only a minor part by urine.
The metabolite can be detected in the urine after 2 to 4 days. [2]
After oral administration pure
glyctrrhizin and glyctrrhizin in glycyrrhiza extract show a significant
difference in gastrointestinal absorption behaviors. In view of serious side
effects such as hypertension and electrolyte disturbances, the study of
pharmacokinetics of glycyrrhizic acid and its metabolites is important. After
oral ingestion, glycyrrhizic acid and its metabolites undergo a complex
kinetic process such as enterohepatic cycling and presystemic metabolism. Following
absorption from intestine, glycyrrhetic acid undergoes bacterial hydrolysis in the
bile. This causes terminal plasma clearance of glycyrrhetic
acid. This study can be used for the assessment of health risk of human
exposure to the products containing glycyrrhizic acid and glycyrrhetic acid.
[3], [4]
Supermicro-pulverization of glycyrrizic
acid influences the solubility and pharmacological action of glycyrrhizic acid.
[5]
The bioavailability of glycyrrhizin
in licorice extract is less than that of pure glycyrrhizin. This is attributed
to the interaction during intestinal absorption between glycyrrhizin
constituent and several components in licorice extract.
This modified bioavailability could
explain the various adverse clinical effects resulting from the chronic oral administration
of glycyrrhizin alone as opposed to licorice extract. These findings were
supported by HPLC method. [6], [7]
Glycyrrhizin and glycyrrhetinic acid
are well known for their anti-inflammatory antiviral and antitumor activities. These
properties are attributed to their affinity for DNA. The spectroscopic evidence
showed DNA binding by glycyrrhizin and glycyrrhetinic acid. DNA binding is
in the order of glycyrrhizin more than glycyrrhetinic acid. [8]
Glycyrrhizic acid is the major
bioactive triterpene glycoside of yashtimadhu-licorice. (Glycyrrhiza
glabra) It possesses a wide range of pharmacological properties. The dry
root of the plant contains 2-24 percent of glycyrrhizic acid. Clinical trials
show that glycyrrhizic acid is active against viral hepatitis and HIV
infections. Its monoammonium salt (glycyram, tussllinar) is used as
anti-inflammatory remedy. The researchers have now synthesized new bioactive
esters of glycyrrhizic acid. They show stronger anti-inflammatory,
antioxidant, anti-allergic, anti-viral, anti-ulcer and anti-tumor effects. The preparation
niglizin (penta-O-nicotinate of glycyrrhizic acid) was extensively studied
clinically for its anti-inflammatory, anti HIV and hepatoprotective
effects. [9]
Oral administration of glycyrrhizin
and extract of yashtimadhu-licorice (Glycyrrhiza glabra) significantly
affects the pharmacokinetics of methotrexate in rats. [10]
Anti-inflammatory, anti-allergic and
antiviral activity of glycyrrhizin
The biological and pharmacological
studies reveal that glycyrrhizin is exerts many pharmacological effects. It
helps synthesize cytokines (interferon-γ and interleukin-12), chemokines. Glycyrrhizin exerts
anti-inflammatory, antioxidant and anti-viral activity. It activates
extra-thymic T cells. It inhibits replication of RNA and DNA of
viruses. While exerting anti-viral activity, glycyrrhizin does not
disrupt normal cells. Glycyrrhizin inactivates herpes simplex virus
particles irreversibly. By stimulating the defense mechanism glycyrrhizin
increases the survival of mice suffering from herpetic
encephalitis. Glycyrrhizin reduces the replication of herpes simplex
virus.
Yashtimadhu-licorice (Glycyrrhiza
glabra) extract, glycyrrhizin (glycyrrhizic acid) and ammonium salt
of glycyrrhizic acid show antiviral activity against Japanese encephalitis
virus (JEV). Purified glycyrrhizin at a concentration of 500 µ grams/ml at 96
hours inhibited plaque formation in all the three (Nakayama, P-20778 and 821564
XY 48) strains of Japanese encephalitis virus. At this
concentration glycyrrhizic acid and its ammonium salt were not toxic
to normal cells. The toxic concentrations of these chemicals were 10,
000 µ grams/ml at 96 hours.
Glycyrrhizin also shows
anti-allergic activity. [11], [12], [13], [14], [15]
Mechanism of anti-inflammatory
activity of glycyrrhizin
Glycyrrhizin shows anti inflammatory
activity. The researchers investigated its effects for parenteral
use against highly pathogenic influenza H5N1 virus replication,
H5N1-induced apoptosis and H5N1-induced pro-inflammatory responses in
(A549) lung epithelial cells. The results revealed that at concentrations of 25
to 50 µg/ml glycyrrhizin strongly interfered with the virus replication
but was less effective in H5N1-induced apoptosis. However at concentrations
of 100 µg/ml and higher concentrations glycyrrhizin was effective
against H5N1-induced apoptosis in lung cells. Glycyrrhizin also diminished
monocyte migration towards H5N1-infected A549 cells. The mechanism of
action of glycyrrhizin can be summarized as follows:
1. Glycyrrhizine shows a strong
anti-inflammatory activity
2. Glycyrrhizine promotes the
synthesis of cortisol
3. Glycyrrhizine inhibits
H5N1-induced formation of reactive free radicals and in turn reduces activation
of NFκB, JNK and p38 i. e. redox-sensitive signalling events involved in
influenza virus replication.
Glycyrrhizin also shows broad
spectrum antiviral activity against:
Various influenza viruses (including
H5N1), Varicella zoster virus (Chicken pox virus), SARS corona virus,
HIV, Hepatitis A, B, C and E viruses. [16], [17], [18]
Yashtimadhu-licorice (Glycyrrhiza
glabra) extract, glycyrrhizic acid, 18 α and 18 β-glycyrrhetinic
acid inhibit the mutagenicity of Salmonella
typhimuricum. [19]
Actions of glycyrrhizin on
osteoporosis
The osteoblastic activity shows
constructive bone forming activity. The osteoclastic activity destroys bone
formation leading to osteoporosis. To evaluate the effect of glycyrrhizic acid
(glycyrrhizin), on osteoporosis, glycyrrhizic acid (glycyrrhizin) was
administered to ovariectomized rats at a dose of 15 mg/kg body weight. The
results obtained indicated that glycyrrhizic acid
(glycyrrhizin) protected the animals from osteoprosis. The
anti-osteoporosis activity of glycyrrhizic acid (glycyrrhizin) was
attributed to estrogen-like activity of glycyrrhizic acid
(glycyrrhizin). Furthermore, glycyrrhizic acid (glycyrrhizin) was
shown to inhibit osteoclastic activity and promote osteoblastic
activity. However when administered at doses smaller than 15 mg/kg body
weight, glycyrrhizic acid (glycyrrhizin) failed to show beneficial
effects on the chemical composition and mechanical properties of bones in
ovariectomized animals. [20], [21]
Action of Glycyrrhizin on skin
A study on Sencar mice showed that
oral feeding of glycyrrhizin offered a substantial protection to the animals
against skin tumerogenesis caused by 7, 12-dimethyl-benz (a)nthracene (DMBA).
The latent period to the onset of the development of skin tumor was
considerably prolonged. Oral feeding of glycyrrhizin in drinking water
also showed the same effect. [22]
Actions of Glycyrrhizin on RS
BALB/c is an albino, laboratory
strain of the house mice developed for research purpose. To evaluate the
efficacy of glycyrrhizin (GRZ) on allergic asthma, BLBA/c mice were sensitized
and challenged with ovalbumin (OVA) to develop hyperresponsiveness of airway:
allergen induced airway obstruction /constriction, hyperreactivity of airway to
methacholine and pulmonary inflammation. The mice were treated orally with 2.5,
5, 10 and 20 mg/kg body weight of glycyrrhizin (GRZ) during or after
ovalbumin challenge. The result showed that glycyrrhizin (GRZ) at 5 mg/kg
body weight markedly inhibited air way obstruction/constriction, air way hypersensitivity,
lung inflammation and infiltration of eosinophils in peribronchial and
perivascular areas. Glycyrrhizin (GRZ) also prevented the reduction of
interferon gamma (IFN-γ), decreased interleukin-5 (IL-5) and eosinophils in the
bronchoalveolar lavage (BAL) fluid. Glycyrrhizin (GRZ) also reduced
ovalbumin-specific Ig E levels and prevented reduction of total Ig G in serum.
The study showed that glycyrrhizin (GRZ) had no effect on serum cortisol
levels. Thus it can be said that glycyrrhizin (GRZ) can be a useful molecule
in future for the treatment of bronchial asthma. [23]
Actionsions of glycyrrhizin on
CVS
Glycyrrhizin was recognized as an
anti-inflammatory agent. Further work showed that its anti-inflammatory effect was
due to its effective anti-thrombin action. To verify this, venous thrombosis
was induced in rats. The rats were then treated with intravenous administration
of glycyrrhizin at doses of 180 mg /kg body weight and 360 mg/kg body weight.
There was a significant reduction in the size and weight of the thrombus.
Glycyrrhizin was also found to prevent thrombosis. In addition glycyrrhizin
above doses of 90 mg/kg body weight caused hemorrhages. [24], [25]
In an experimental study male
Sprague-Dawley rats received drinking water containing 0.1 mg/ml and 1 mg/ml for
12 weeks. Their blood pressure was recorded every three weeks and serum sodium
and potassium were measured at the beginning and at the end of experiment.
Right atrial pressure was recorded at the end of 12 weeks. The animals were
then sacrificed. There was a significant increase in the mean right atrial
pressure from 2.69 mm of Hg to 4.7 mm of Hg associated with increase in sodium
and decrease in potassium. Histological examination showed increased thickness
of pulmonary arterial wall. Thus glycyrrhizic acid caused an increase in right
atrial pressure as well as thickening of the pulmonary vessels suggesting
pulmonary hypertension [26]
In a study, infusion of glycyrrhizic
acid and its synthetic analogue carbenoxolone into the lateral ventricle of the
brain of rat at a dose less than the subcutaneous dose produced hypertension.
Furthermore the hypertension produced by oral administration of these compounds
was blocked by mineralocorticoid antagonist, RU 28318 potassium salt. (RU 28318
is a potent and selective antagonist for the mineralocorticoid receptor.
It inhibits aldosterone production and selectively
decreases mineralocorticoid receptor binding in the hippocampus of
adrenalectomised rats. It decreases blood pressure in female rats following
central administration) While oral administration caused saline polydipsia and polyuria
typical of chronic systemic mineralocorticoid excess, the intraventricular
administration of licorice derivatives produced hypertension without affecting
saline appetite. These findings suggest central role in the production of hypertension
by licorice derivatives. [27]
Glycyrrhizic acid is hydrolyzed in
the intestine to glycyrrhetic acid which inhibits the enzyme 11
beta-hydroxysteroid dehydrogenase as well as some other enzymes involved in the
metabolism corticosteroids. This inhibition leads to increased levels of
cortisol in the kidneys and mineralocorticoid in selective tissues. A high
intake of licorice can cause hypermineralocorticoidism with sodium retention,
loss of potassium, water retention, edema, hypertension and depression of the
renenin-angiotensin-aldosterone system. As a result a number of clinical
symptoms have been observed. There is a great variation in the susceptibility
to glycyrrhizic acid. In sensitive individuals a regular daily intake of 100 mg
of glycyrrhizic acid which corresponds to 50 g of licorice may be enough to
produce adverse effects. Individuals who
consume sweets containing 400 mg of glycyrrhizic acid daily experience adverse
effects. [28]
In a study on rats the stimulating
effects of glycyrrhizic acid (GZA) and 18 beta-glycyrrhetinic acid (GTA) on
intakes of water and sodium chloride resembled those caused by the
administration of excessive amounts of mineralocorticoid. The results suggest
that GZA- or GTA-induced drinking behavior is mediated by circulating
glucocorticoids. After licorice blockade of 11-beta hydroxysteroid
dehydrogenase, the peripheral and central mineralocorticoid receptors are no
longer protected from glucocorticoid action. [29]
A case report:
The patients with anorexia nervosa
show decreased appetite. Their food intake is low. They are constipated. They frequently
consume laxatives/purgatives. They have life-threatening electrolyte disturbance
such as hypokalemia. Severe hypokalemia was induced in a patient of anorexia
nervosa ingesting yashtimadhu-licorice (Glycyrrhiza glabra)
approximately 20 g a day. The diagnosis of licorice induced
pseudohyperaldosteronism was confirmed by cessation of licorice intake and
re-exposure to licorice. Cessation of the licorice intake normalized potassium,
renin and aldosterone levels in the blood and cortisol/cortisone ratio in the
urine. Re-exposure altered these values again. Prolonged intake of low daily
doses licorice can show this type of toxicity, suggesting high glycyrryzin
sensitivity. [30]
Actions of glycyrrhizin on liver
diseases
To evaluate the effects
of yashtimadhu-licorice (Glycyrrhiza glabra) in patients suffering
from liver disease caused by chronic hepatitis C (HCV) infection with
compensated cirrhosis, forty four patients were treated with intravenous glycyrrhizin
at doses, 200 mg/week for 6 weeks, 240 mg/week for 3 weeks, and placebo for 3
weeks. Glycyrrhizin and its metabolite glycyrrhetinic acid reduced/retarded the
progression of liver disease. In all patients body weight, blood pressure,
blood levels of sodium, potassium, cortisol, dehydroepiandrosterone sulphate
(DHEA-S), renin and aldesterone were measured before and 0 and 4 weeks after
treatment. No changes were observed in placebo group. In patients receiving
1200 mg or more of glycyrrhizin, there was a significant rise in blood
pressure; pseudo-
aldosteronism and hypokalemia were observed. [31]
Medicinal uses of glycyrrhizin
Glycyrrhizin is useful in viral
hepatitis. The Japanese administer glycyrrhizin intravenously for the
treatment of chronic hepatitis and cirrhosis. A small trial revealed that early
treatment with glycyrrhizin might prevent the onset and progression of
auto-immune hepatitis. [32], [33]
Glycyrrhizin (glycyrrhizic acid) is
one of the leading natural compounds for clinical trials of chronic viral
hepatitis and HIV infections. Its monoammonium salt (glycyram, tusilinar) is
used as anti-inflammatory, anti-allergic remedy. Many pharmacologically
effective synthetic derivatives of glycyrrhizin (glycyrrhizic acid)
are now available for medicinal use. Pharmacologically they are more
effective than the natural constituents of licorice. Preparation niglizin
(penta-O-niconate of glycyrrhizin) showed a strong anti-inflammatory activity
and is of for studies as hepatoprotector and inhibitor of HIV. Glycyrrhizin and
glycyrrhetinic acid exert virustatic action on hepatitis B and hepatitis C viruses.
Their action depends on inhibition of intrahepatic transport and sialyzation of
hepatitis B virus. Monoammonium salt of glycyrrhizin shows only marginal
activity against hepatitis C virus. In Japan glycyrrhizin is used to treat
hepatitis C infection in patients showing no response to α-interferon.
[34], [35], [36]
Adverse effects of glycyrrhizin
The most widely reported side effect
of glycyrrhizin is fluid retention. This is due to cortisol synthesis,
inhibition of cortisol metabolism within
the kidney and subsequent stimulation of mineralocorticoid receptors. The other
side effects include headache, paralysis, Transient loss of vision, torsades de
pointes (an uncommon variety of ventricular
tachycardia), tachycardia, cardiac arrest, hypokalaemia, reduced levels of
testosterone, premature birth, acute
renal failure, muscle weakness and myopathy. [37]
Glycyrrhetinic acid (GA)
Molecular formula: C30H46O4
Structural formula:
Glycyrrhetinic acid is also
known as Glycyrrhetic acid, enoxolone, uralenic acid, biosolone and
by many more chemical names. It is a pentacyclic triterpenoid derivative
of β amyrin type obtained by hydrolysis of glycyrrhizic acid obtained from
the herb yashtimadhu-licorice (Glycyrrhiza glabra). It is used in food
industry as a flavoring agent. It masks bitter taste. However glycyrrhetic
acid is more than just a flavor. It has many important medicinal
properties. [38], [39], [40]
Because glycyrrhetic acid is
200-1000 times more potent inhibitor of 11-β-hydroxysteroid dehydrogenase
compared to glycyrrhizic acid, the pharmacokinetics of glycyrrhetic acid are
relevant in toxicological perspective. After oral administration glycyrrhetic
acid is absorbed and transported to the liver. In the liver it is metabolized
into glucuronide and sulfate conjugates. These conjugates are transported to
the duodenum via bile. The conjugates are hydrolyzed to glycyrrhetic acid
by commensal bacteria. The glycyrrhetic acid is then reabsorbed. This
enterohepatic recycling causes delay in its excretion. After repeated administration glycyrrhetic
acid might accumulate and cause glycyrrhetic acid-induced adverse
effects. [41], [42]
Glycyrrhetinic acid is the major
metabolite formed when glycyrrhizin is administered orally. In rats
oral administration of glycyrrhetinic acid (GA) restrains the metabolism
of cortisone (E) and cortisol (F). This effect may be related to the
inhibitory effect by glycyrrhetinic acid (GA) on
11 β-hydroxysteroid dehydrogenase (11 β-HSD) resulting in inhibition of
the conversion of cortisol to the inactive steroid cortisone. Therefore the
levels of cortisol are elevated. In addition, GA inhibits 17, 20-lyase and
17 β-hydroxysteroid dehydrogenase, resulting in decreased conversion of
17-hydroxyprogesterone to androstenendione and subsequently androstenendione
to testosterone. A great care should be taken while using steroids,
steroid analogues for a patient using Yashtimadhu-licorice (Glycyrrhiza
glabra) or Yashtimadhu-licorice formulations for therapy. [43],
[44], [45]
Pure glycyrrhetinic acid (GA)
administered orally at 500 mg/day to ten healthy normotensive volunteers from
days 3-10 of the study exerted pronounced mineralocorticoid activity. While
plasma cortisol levels were unchanged, urinary excretion of free
cortisol was elevated; even though the levels of plasma cortisone and urinary
free cortisone were markedly decreased. These results provide a direct support
for the hypothesis that glycyrrhetinic acid (GA) inhibits 11-β-dehydrogenase
activity blocking the conversion of cortisol to cortisone. [46]
Glycyrrhetinic acid masks the bitter
taste of aloe and quinine. It has antiviral, antibacterial and antifungal
activity. [Hence Yashtimadhu-licorice- Glycyrrhiza glabra is
combined with bitter drugs for the treatment of oral infections, viral and
bacterial respiratory infections.] Glycyrrhetinic acid is also useful for the
treatment of fungal, protozoal and parasitic infections. [47], [48], [49]
To evaluate antitussive activity of
glycyrrhizin, glycyrrhetinic acid and Liquiritigenin, hack was induced in rats
by using sulphur dioxide (SO2). The
animals were then treated with these phytochemicals. They displayed the
antitussive and expectorant activity. A study showed that the derivatives
of glycyrrhetinic acid also displayed similar activities. [50]
Yashtimadhu-licorice (Glycyrrhiza
glabra) is the most commonly used herbal drug in medical
practice. Glycyrrhetinic acid (GA) is an important bioactive
phytochemical. It has anti-inflammatory, anti-oxidant, antiviral,
antibacterial, antifungal, antiprotozoal and antiparasitic and antipeptic ulcer
properties. It has adrenal cortical hormone like function. Clinical trials
clearly show that glycyrrhetinic acid is effective against all types of
dermatitis, purulent scar disease and hair follicle infection. It can cure
gingivitis, oesophagitis, gastritis and peptic ulcer.
Glycyrrhetinic acid is useful to
control dyslipidemia and prevent atherosclerosis.
Glycyrrhetinic acid inhibits many enzymes
in the metabolic process of corticosteroids. [51], [52]
Glycyrrhetinic acid is used for the
treatment of encephalitis caused by Japanese encephalitis virus. [53]
Medicinal use
of Yashtimadhu-licorice (Glycyrrhiza glabra) is not safe in
patients with impaired renal function. In a study on seven patients with
anuria who were on hemodialysis, administration of glycyrrhetinic acid at a
dose 1 g/ day markedly decreased the plasma potassium concentrations. [54]
Day by day yashtimadhu-licorice (Glycyrrhiza
glabra) abuse is increasing. The abuse leads to severe and sometimes serious
complications. Metabolic products of glycyrrhetinic acid contained
in yashtimadhu-licorice (Glycyrrhiza glabra), are excreted in the
urine. To detect licorice toxicity, the researchers have developed a urinary
18-β- GA assay based on chromatography and mass spectrometry (GCMS) with
sufficient sensitivity to detect 18-β- GA at low concentrations.
The assay has been validated in four healthy volunteers (not using licorice)
and two patients of licorice abuse who developed licorice toxicity. [55]
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