TY - JOUR
T1 - Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations
T2 - A Narrative Review
AU - Yoshino, Tetsuhiro
AU - Shimada, Saori
AU - Homma, Masato
AU - Makino, Toshiaki
AU - Mimura, Masaru
AU - Watanabe, Kenji
N1 - Funding Information:
This work was supported by a Grant-in-Aid from the Research Project for Improving Quality in Healthcare and Collecting Scientific Evidence on Integrative Medicine from AMED under grant numbers JP17lk0310036h0001, JP18lk0310049h0001, and JP19lk0310064h0001. The authors declare that this study received funding from Tsumura Co. In addition, TM received research grant supports from Tsumura & Co., Kracie Pharmaceuticals, JPS Pharmaceuticals, and Taisho Pharmaceutical Holdings. MM received research grant supports from Tsumura & Co. and Kracie Pharmaceuticals. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of article, or the decision
Publisher Copyright:
© Copyright © 2021 Yoshino, Shimada, Homma, Makino, Mimura and Watanabe.
PY - 2021/9/17
Y1 - 2021/9/17
N2 - Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.
AB - Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.
KW - Japanese Kampo medicine
KW - hypokalemia
KW - licorice
KW - pharmacokinetics
KW - pseudoaldosteronism
UR - http://www.scopus.com/inward/record.url?scp=85116318212&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116318212&partnerID=8YFLogxK
U2 - 10.3389/fnut.2021.719197
DO - 10.3389/fnut.2021.719197
M3 - Review article
AN - SCOPUS:85116318212
SN - 2296-861X
VL - 8
JO - Frontiers in Nutrition
JF - Frontiers in Nutrition
M1 - 719197
ER -