Inhibition of UDP-glucuronosyltransferase (UGT)-mediated glycyrrhetinic acid 3-O-glucuronidation by polyphenols and triterpenoids

• Published in: Drug metabolism and pharmacokinetics 2017-08, Vol.32 (4), p.218-223
• Main Authors: Koyama, Mayuko, Shirahata, Tatsuya, Hirashima, Rika, Kobayashi, Yoshinori, Itoh, Tomoo, Fujiwara, Ryoichi
• Format: Article
• Language: English
• Subjects: Adverse reaction; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Glucuronidation; Glucuronide; Glucuronides - metabolism; Glucuronosyltransferase - antagonists & inhibitors; Glucuronosyltransferase - metabolism; Glycyrrhetinic acid; Glycyrrhetinic Acid - metabolism; Glycyrrhizin; Humans; Licorice; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Molecular Structure; Natural medicine; Polyphenols - pharmacology; Pseudohyperaldosteronism; Structure-Activity Relationship; Triterpenes - pharmacology; UDP-Glucuronosyltransferase; UGT
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2017.04.003

Glycyrrhetinic acid (GA) is an active metabolite of glycyrrhizin, which is a main constituent in licorice (Glycyrrhiza glabra). While GA exhibits a wide variety of pharmacological activities in the body, it is converted to a toxic metabolite GA 3-O-glucuronide by hepatic UDP-glucuronosyltransferases (UGTs). To avoid the development of the toxic metabolite-induced pseudohyperaldosteronism (pseudoaldosteronism), there is a limitation in maximum daily dosage of licorice and in combined usage of other glycyrrhizin-containing natural medicine. In this study, we investigated the inhibitory effects of various polyphenols and triterpenoids on the UGT-mediated GA 3-O-glucuronidation. In human liver microsomes, UGT-mediated GA glucuronidation was significantly inhibited by protopanaxadiol with an IC50 value of 59.2 μM. Isoliquiritigenin, rosmarinic acid, alisol B, alisol acetate, and catechin moderately inhibited the GA glucuronidation with IC50 values of 96.4 μM, 125 μM, 160 μM, 163 μM, and 164 μM. Other tested 19 polyphenols and triterpenoids, including liquiritigenin, did not inhibit UGT-mediated GA glucuronidation in human liver microsomes. Our data indicate that relatively higher dosage of licorice can be used without a risk of developing pseudohyperaldosteronism in combination of natural medicine containing protopanaxadiol such as Panax ginseng. Furthermore, supplemental protopanaxadiol and isoliquiritigenin might be useful in preventing licorice-inducing pseudoaldosteronism. [Display omitted]