3--18-Glycyrrhetinic Acid or Its Glucuronide, the Metabolites of Glycyrrhizinic Acid with Individual Differences, Correlated with Diagnostic Marker for Licorice-Induced Pseudoaldosteronism in Humans.

Licorice is a crude drug that is used in traditional Japanese Kampo medicine and is also used as a sweetener. Occasionally, it causes pseudoaldosteronism (PsA) as a side effect. The major symptoms include hypokalemia, hypertension, edema, and low plasma aldosterone levels. PsA might be caused by the metabolites of glycyrrhizinic acid (GL), a component of licorice. The development of PsA markedly varies among individuals; however, the factors that cause these individual differences remain unknown. In this study, 78 patients who consumed Kampo medicines containing licorice were enrolled, and their laboratory data, including serum potassium levels, plasma aldosterone concentrations (PAC), and the concentrations of GL metabolites in the residual blood and/or urine samples were evaluated. Of the 78 participants, 18-glycyrrhetinic acid (GA), 3--GA, 3-oxo-GA, 18-glycyrrhetinyl-30--glucuronide (GA30G), and 3GA30G were detected in the serum samples of 65, 47, 63, 62, and three participants, respectively. Of the 29 urine samples collected, GA30G and 3-GA30G were detected in 27 and 19 samples. 3--GA30G is a newly found GL metabolite. Moreover, 3GA, 3-oxo-GA, and 3--GA30G were identified in human samples for the first time. High individual differences were found in the appearances of 3--GA in serum and 3--GA30G in urine, and the concentrations of these metabolites were correlated with serum PsA markers. The inhibitory titers of 3--GA, 3-oxo-GA, GA30G, and 3GA30G on human 11-hydroxysteroid dehydrogenase type 2 were almost similar. These findings suggest that 3GA and/or 3--GA30G are associated with individual differences in the development of PsA. SIGNIFICANCE STATEMENT: In this study, we detected 3--18-glycyrrhetinic acid (3--GA) in human serum for the first time. We also identified 3--18-glycyrrhetinyl-30--glucuronide (3--GA30G) as a novel glycyrrhizinic acid (GL) metabolite in human urine. These GL metabolite levels showed correlations with markers of PsA. Additionally, there are individual differences in whether they appear in the serum/urine. In conclusion, 3--GA/3-GA30G correlates with individual differences in the development of PsA.