3-Monoglucuronyl-glycyrrhretinic acid is a substrate of organic anion transporters expressed in tubular epithelial cells and plays important roles in licorice-induced pseudoaldosteronism by inhibiting 11β-hydroxysteroid dehydrogenase 2.

Abstract

Licorice (glycyrrhiza root) has been used as a herbal medicine worldwide with its main active constituent being glycyrrhizin (GL). Licorice sometimes causes adverse effects such as inducing pseudoaldosteronism by inhibiting type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2) caused by glycyrrhetinic acid (GA), a major metabolite of GL. In this study we compared the inhibitory effects of GA, GL, and 3-monoglucuronyl-glycyrrhetinic acid (3MGA), another metabolite of GL, on 11β-HSD2 activity by using microsomes and rat kidney tissue slices. GA, 3MGA, and GL inhibited 11β-HSD2 in rat kidney microsomes, with IC(50) values of 0.32, 0.26, and 2.2 μM, respectively. However, the inhibitory activity of these compounds was reduced markedly, in the slices, in a medium containing 5% bovine serum albumin. Assays using human embryonic kidney 293 cells with transient transformation in transporter genes showed that 3MGA is a substrate of human organic anion transporter (OAT) 1, human OAT3, and human organic anion-transporting peptide 4C1, whereas GA is not. When GA (100 mg/kg/day) was administered orally for 16 days to Eisai hyperbilirubinemic rats, plasma concentrations and urinary excretion of 3MGA were significantly higher, whereas the activity of 11β-HSD2 in kidney microsomes was significantly lower compared with Sprague Dawley rats. These results suggest that 3MGA is actively transported into tubules through OATs, resulting in the inhibition of 11β-HSD2. Because the plasma level of 3MGA depends on the function of hepatic transporters, monitoring 3MGA levels in plasma or urine may be useful for preventing pseudoaldosteronism when licorice or GL is prescribed to patients.

• Authors: Toshiaki Makino, Kyoko Okajima, Rie Uebayashi, Nobuhiro Ohtake, Katsuhisa Inoue, Hajime Mizukami
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 342 Issue 2 Pg. 297-304 (Aug 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22543032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Organic Anion Transporters
• glycyrrhetyl 3-monoglucuronide
• Glycyrrhizic Acid
• 11-beta-Hydroxysteroid Dehydrogenase Type 2
• Glycyrrhetinic Acid

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 2 (antagonists & inhibitors, metabolism)
• Animals
• Cell Line, Transformed
• Epithelial Cells (enzymology, metabolism)
• Glycyrrhetinic Acid (analogs & derivatives, blood, metabolism, pharmacology, urine)
• Glycyrrhiza (toxicity)
• Glycyrrhizic Acid (metabolism, pharmacology)
• HEK293 Cells
• Humans
• Kidney (drug effects, enzymology, metabolism)
• Liddle Syndrome (chemically induced, enzymology, metabolism)
• Liver (drug effects, enzymology, metabolism)
• Male
• Microsomes (drug effects, enzymology, metabolism)
• Organic Anion Transporters (metabolism)
• Plants, Medicinal (toxicity)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar