Abstract
Licorice-induced pseudoaldosteronism is a common adverse effect in traditional Japanese Kampo medicine, and 3-monoglucuronyl glycyrrhetinic acid (3MGA) was considered as a causative agent of it. Previously, we found 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), one of the metabolites of glycyrrhizin (GL) in the urine of Eisai hyperbilirubinuria rats (EHBRs) treated with glycyrrhetinic acid (GA), and suggested that it is also a possible causative agent of pseudoaldosteronism. The discovery of 1 also suggested that there might be other metabolites of GA as causal candidates. In this study, we found 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2) and 18β-glycyrrhetyl-3-O-sulfate (3) in EHBRs’ urine. 2 and 3 more strongly inhibited rat type 2 11β-hydroxysteroid dehydrogenase than 1 did in vitro. When EHBRs were orally treated with GA, GA and 1–3 in plasma and 1–3 in urine were detected; the levels of 3MGA were quite low. 2 and 3 were shown to be the substrates of organic anion transporter (OAT) 1 and OAT3. In the plasma of a patient suffering from pseudoaldosteronism with rhabdomyolysis due to licorice, we found 8.6 µM of 3, 1.3 µM of GA, and 87 nM of 2, but 1, GL, and 3MGA were not detected. These findings suggest that 18β-glycyrrhetyl-3-O-sulfate (3) is an alternative causative agent of pseudoaldosteronism, rather than 3MGA and 1.
Highlights
It is well known that excessive intake of licorice induces pseudoaldosteronism, which is characterized by peripheral edema, hypokalemia, and hypertension[1]
We found that 3-monoglucuronyl glycyrrhetinic acid (3MGA) did not appear in the plasma or urine of Sprague-Dawley (SD) rats treated with glycyrrhetinic acid (GA), but did appear in rats with liver fibrosis and in multidrug resistance-associated protein (Mrp) 2-deficient Eisai hyperbilirubinuria rats (EHBRs)
We developed an anti-3MGA-monoclonal antibody and an enzyme-linked immunosorbent assay (ELISA) to detect 3MGA in the blood or urine of patients who took licorice, in order to prevent pseudoaldosteronism by predicting the individual body constitution causing this condition without using expensive instruments such as LC-MS/MS18
Summary
It is well known that excessive intake of licorice induces pseudoaldosteronism, which is characterized by peripheral edema, hypokalemia, and hypertension[1]. From these results, we developed an anti-3MGA-monoclonal antibody (mAb) and an enzyme-linked immunosorbent assay (ELISA) to detect 3MGA in the blood or urine of patients who took licorice, in order to prevent pseudoaldosteronism by predicting the individual body constitution causing this condition without using expensive instruments such as LC-MS/MS18. The inhibitory titer of 1 on 11β-HSD2 was lower than that of 3MGA, its plasma concentration in EHBRs treated with GA was higher, making it a candidate for the causative agent of licorice-induced pseudoaldosteronism[18]
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