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:


Glycyrrhizic Acid.svg


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 structure.svg


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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