3-Monoglucuronyl Glycyrrhretinic Acid Is a Possible Marker Compound Related to Licorice-Induced Pseudoaldosteronism

Abstract

One of the most common adverse effects of traditional Japanese kampo and traditional Chinese medicine is pseudoaldosteronism caused by licorice. In this review, the authors describe the mechanisms of licorice-induced pseudoaldosteronism by the pharmacokinetics of chemical constituents and its metabolites containing licorice. Glycyrrhizin (GL), the main constituent of licorice, is absorbed as glycyrrhetinic acid (GA), which is a metabolite of GL produced by enterobacteria before its release into the circulation. Circulating GA is metabolized in the liver to become 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which is excreted into the bile via multidrug resistance protein 2 (Mrp2). If Mrp2 function is damaged for some reason, 3MGA is secreted from the liver into the circulation, and excreted into the urine via organic anion transporters expressed at the basolateral side of tubular epithelial cells. Circulating GA cannot be excreted into the urine since GA binds highly to serum albumin and thus does not pass through glomerular filtration and is not a substrate of transporters expressed on tubular epithelial cells. Licorice-induced pseudoaldosteronism develops due to the inhibition of type 2 11β-hydrosteroid dehydrogenase (11β-HSD2) which results in the accumulation of cortisol in tubular epithelial cells that activate mineral corticoid receptors to stimulate the excretion of potassium that results in hypokalemia. GA, unlike 3MGA, cannot pass through tubular epithelial cells and cannot inhibit the enzyme in the cells. Therefore, 3MGA may be a genuine causative agent for licorice-induced pseudoaldosteronism. When licorice is used, 3MGA in plasma or urine could function as a marker compound to prevent the adverse effects.

Posterior Reversible Encephalopathy Syndrome Associated With Licorice Consumption: A Case Report in a 10-Year-Old Boy

“…This condition is similar to the so-called "syndrome of apparent mineralocorticoid excess." 5,9,10 There have been several reports of hypertension in adult patients associated with abuse of licorice. However, the amount of licorice daily intake that makes hypertension a risk is not precisely known.…”

Usefulness of mineralocorticoid receptor antagonists, rather than angiotensin II receptor blockers, for the prevention and treatment of licorice‐induced pseudoaldosteronism

“…Also, patients with essential hypertension are more sensitive to the inhibition of 11β‐HSD by licorice than normotensive subjects, and this inhibition causes more clinical symptoms in women than in men . Concerning the active component, Makino reported that 3‐monoglucuronyl‐glycyrrhetinic acid, a metabolite of glycyrrhizin, may be a genuine causative agent of licorice‐induced pseudoaldosteronism .…”

Pharmacokinetic Profiles of Active Components After Oral Administration of a Kampo Medicine, Shakuyakukanzoto, to Healthy Adult Japanese Volunteers

“…Further, the analgesic effect of SKT is believed to suppress the transmission of pain to the upper central nervous system by suppressing the release of substance P from the primary afferent fiber via the activation the descending inhibitory 5‐HT and NE neurons in the posterior horn of the spinal cord, and these active components are believed to be Paeoniae radix‐derived ALB and PAE . Further, whereas GA contributes to the efficacy of SKT, GA has also been thought, along with 3MGA, to be a causal component in hypokalemia . For these effects to be manifested, it is necessary at the very least for the active components to transition into the blood after SKT is orally administered.…”

“…Glycyrrhizae radix‐derived glycyrrhetic acid (GA), glycycoumarin (GCM), and isoliquiritigenin (ILG) are presumed to be active components, which are responsible for anticonvulsive, analgesic, and muscle‐relaxant effects, and Paeoniae radix‐derived paeoniflorin (PAE) and albiflorin (ALB) are presumed to be active components that are responsible for antinociceptive effects . In contrast, long‐term excessive ingestion of Glycyrrhizae radix is known to cause pseudoaldosteronism or hypokalemia, and it has been suggested that the causal components could be GA and glycyrrhetic acid‐3‐ O ‐monoglucuronide (3MGA), which is a metabolite of glycyrrhizic acid (GL) present in Glycyrrhizae radix …”

“…6 In contrast, long-term excessive ingestion of Glycyrrhizae radix is known to cause pseudoaldosteronism or hypokalemia, [11][12][13][14] and it has been suggested that the causal components could be GA and glycyrrhetic acid-3-O-monoglucuronide (3MGA), which is a metabolite of glycyrrhizic acid (GL) present in Glycyrrhizae radix. [15][16][17][18] To evaluate the pharmacological action and safety of SKT, it is important to determine the pharmacokinetics of active components after the administration. To date, Paeoniae radixderived components ALB and PAE and the Glycyrrhizae radixderived components GCM, ILG, GA, and 3MGA have been detected in the blood of rats after single oral administration of SKT.…”