- 1 MINERALOCORTICOID EFFECT
The glycyrrhetinic acid (GA) constituent in licorice (and its metabolite 3-monoglucuronyl-glycyrrhetinic acid) inhibits the enzyme 11HSD, which catalyses the conversion of cortisol into its inactive metabolite, cortisone. This results in delayed excretion and prolonged activity of cortisol. Additionally, glycyrrhizin (GL) and GA bind to mineralocorticoid and glucocorticoid receptors and may displace cortisol from its carrier molecule, transcortin.
As cortisol levels rise, they stimulate mineralocorticoid receptors in the distal renal tubule. This creates pseudohyperaldosteronism, which has the same clinical features as primary aldosteronism, including sodium retention, fluid retention and oedema, hypertension, hypokalaemia and metabolic alkalosis.
A case report suggests that the symptoms occur despite low plasma levels of aldosterone. Decreased plasma renin activity and increased cortisol levels result in vasoconstriction of vascular smooth muscle, which may further exacerbate the hypertensive effects. This may be of particular significance in patients with prolonged intestinal transit time where GA levels can accumulate.
The anti-inflammatory action of glycyrrhetinic acid is largely mediated by cortisol, an endogenous hormone with anti-inflammatory action. Several studies have found that GA inhibits the activity of 11 HSD and hepatic delta-4-5-beta-steroid reductase, preventing the conversion of cortisol to its inactive metabolite, cortisone. As such, cortisol activity is prolonged and levels may rise, thereby increasing its anti-inflammatory effects.
For this reason licorice has also been investigated for its ability to potentiate the effects of steroid medications.
This mechanism alone does not fully account for the anti-inflammatory effects of licorice as oral doses of glycyrrhizin also appear to exert an effect in adrenalectomised rats. The deglycyrrhizinated licorice also exerts anti-inflammatory effects. Steroid-like activity has also been attributed to the liquiritin constituent and in vitro studies of G. inflata reveal that the licochalcone flavonoids A and B inhibit the formation of leukotrienes B4 and C4, cyto-B-induced lysosomal enzyme, platelet-activating factor, N-formyl-methionyl-leucyl-phenylalanineand calcium ionophore A. The anti-inflammatory response may also be enhanced by inhibition of the generation of reactive oxygen by neutrophils.
Early investigation into the mucoprotective qualities of licorice led to the development of an anti-inflammatory and antiulcer medication, carbenoxolone, an ester derivative of GA, used to treat gastric and oesophageal ulcer disease. Researchers have suggested that it may exert its mucoprotective effects by increasing mucosal blood flow as well as mucus production, and by interfering with gastric prostanoid synthesis. Animal studies indicate that licorice preparations such as deglycyrrhizinated licorice improve the environment in the stomach by increasing mucus production, thereby allowing for proliferation of tissue and healing to occur. DGL increases mucus production by increasing the number of fundus glands and the number of mucus-secreting cells on each gland.
The increase in mucus production seen with carbenoxolone and licorice appears to occur in a number of epithelial tissues other than the digestive tract. It has been reported in the lungs and also bladder, according to in vivo studies, and in the trachea, accounting for its expectorant properties.
Licorice demonstrates the ability to promote mucosal repair and reduce symptoms of active ulcer.
The anti-ulcer effects of licorice are due to inhibition of 15-hydroxyprostaglandin dehydrogenase, (which converts PGE2 and F2α to heir inactive forms) and delta 13-PG reductase. Licorice-derived compounds therefore increase the local concentration of PGs that promote mucus secretion and cell proliferation in the stomach, leading to healing of ulcers.
Anti-inflammatory activity (as described above) further contributes to the herb’s symptom-relieving action.
Both oral and injectable dose forms of licorice have been tested and found to have activity against a range of viruses. This effect is mediated by the constituents glycyrrhizin and glycyrrhetinic acid. It should be noted that current studies focus largely on GL, which is converted in the gut to GA and may not produce the same results as those demonstrated for glycyrrhizin in vitro.
In vitro studies have shown GL to inhibit SARS-CV (clinical isolates FFM-1 and FFM-2) replication by inhibiting adsorption and penetration of the virus in the early steps of the replicative cycle. Glycyrrhizin was most effective when given both during and after the adsorption period. High concentrations of GL (4000 mg/L) were found to completely block replication of the virus. The ability of glycyrrhizin to reduce platelet accumulation in the lungs may also support this use and provide a possible therapeutic option for further investigation.
HIV Preliminary evidence indicates that intravenous administration of GL may reduce replication of HIV. High-dose GL (1600 mg/day) was most effective in reducing HIV type 1 p24 antigen and increasing lymphocytes. In vitro, glycyrrhizin has the potential to inhibit viral replication in cultures of peripheral blood mononuclear cells from HIV-infected patients infected with a non-syncytium-inducing variant of HIV.
Epstein-Barr virus In vitro studies suggest that glycyrrhizin may interfere with an early step of the EBV replication cycle (possibly penetration). Herpes simplex virus 1 In Kaposi sarcoma-associated herpes virus (KSHV), glycyrrhizin reduced the synthesis of a viral latency protein and induced apoptosis of infected cells terminating KSHV latent infection of B lymphocytes. Early in vitro studies found that GL inactivated HSV irreversibly. Animal studies show that intraperitoneal administration of glycyrrhizin reduces HSV-1 viral replication and improves survival from herpetic encephalitis in mice. Whether glycyrrhizin may act against other latent herpes viruses or be suitable for clinical use against KSHV requires further elucidation.
A number of constituents in licorice, including phenolic compounds (glicophenone and glicoisoflavanone), licochalcone A and isoflavones, were found to have antibacterial effects on MRSA and MSSA in vitro.
Expectorant effects may be attributed to the ability of licorice to stimulate tracheal mucus secretion, facilitating the elimination of mucus from the respiratory tract.
In animal studies licorice produces a persistent antitussive effect, which is mediated by liquiritin apioside in the earlier phase and liquiritin and liquiritigenin (a metabolite of liquiritin apioside) in the later phase.
In vitro research has identified seven antioxidant compounds from an acetone extract of licorice: four isoflavans (hispaglabridin A, hispaglabridin B, glabridin and 4′-0-methylglabridin), two chalcones (isoprenylchalcone derivative and isoliquiritigenin) and an isoflavone (formononetin). Isoflavones from licorice were also shown to be effective in protecting mitochondrial function against oxidative stresses.
Reduces lipid peroxidation Macrophage-mediated oxidation of LDL-cholesterol plays a major role in early atherogenesis. In animal models glabridin accumulates in macrophages and inhibits macrophage-mediated oxidation of LDL by up to 80%. Deglycyrrhizinated licorice (100 mg/day for 2 weeks) was found to reduce lipid peroxidation of LDL-cholesterol after 1 week’s use according to a placebo-controlled trial.
Licorice has demonstrated potent anti-angiogenic and antitumour activity in animal studies. Animal and in vitro studies have shown licorice components to be effective in reducing the occurrence and number of tumour cells in several cancer models, inducing apoptosis and potentiating the effect of paclitaxel and vinblastine chemotherapy. In vitro research reveals that chalconeand isoliquiritigenin significantly inhibit the proliferation of prostate cancer cell lines in a dose- and time-dependent manner and that beta-hydroxy-DHP inhibits breast and prostate tumour cells. Isoliquiritigenin has also been shown to significantly inhibit the proliferation of lung and colon cancer cells, restrain cell cycle progression and induce apoptosis.
Although the exact mechanism of action is still being determined, a 2001 review indicates that licorice and its derivatives may protect against carcinogen-induced DNA damage and that GA is an inhibitor of lipo-oxygenase and cyclo-oxygenase, inhibits protein kinase C, and down-regulates the epidermal growth factor receptor.
Glycyrrhiza glabra has shown promise as a memory-enhancing agent in both exteroceptive and interoceptive behavioural models of memory in mice. The effect is possibly due to facilitation of cholinergic transmission in the mouse brain. Effects on humans have yet to be demonstrated; however, a clinical trial of 170 elderly subjects is currently planned.
Animal studies demonstrate that licorice protects hepatocytes by inhibiting experimentally induced lipid peroxidation. In vitro studies have shown hepatoprotective effects of GL against aflatoxin B1 -induced cytotoxicity in human hepatoma cells and animal studies have shown GA exerts hepatoprotective effects against carbon tetrachloride-induced liver injury.
Several mechanisms appear to be responsible for the hepatoprotective effect. Glycyrrhizicacid enhances the detoxifying activity of the liver enzyme CYP1A1 and glutathione S-transferase and protects against oxidative stress, when induced by aflatoxin.
Animal studies have found that GA inhibits expression of the liver enzyme CYP2E1. Once again, antioxidant mechanisms appear to be involved, as GA prevented glutathione depletion, an increase in ALT, AST activity, and hepatic lipid peroxidation in a dose-dependent manner when carbon tetrachloride exposure occurred. In addition isoliquiritigenin may stimulate the proliferation of human hepatocytes according to in vitro studies.
Isoliquiritigenin purified from licorice has been shown to inhibit platelet aggregation in vitro and in vivo. Whether the effect is clinically significant for licorice remains to be determined. New data indicates that GL is an effective thrombin inhibitor in vivo.