J Ethnopharmacol. 2015 Mar 13;162:134-9. doi: 10.1016/j.jep.2014.12.043. Epub 2014 Dec 31.

A protective mechanism of licorice (Glycyrrhiza uralensis): isoliquiritigenin stimulates detoxification system via Nrf2 activation.

Gong H1, Zhang BK1, Yan M2, Fang PF1, Li HD1, Hu CP3, Yang Y3, Cao P4, Jiang P1, Fan XR5.

• 1Clinical Pharmacy and Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, 139# Middle Renmin Road, Changsha, Hunan Province 410011, China; School of Pharmaceutical Sciences, Central South University, 172# Tong Zipo Road, Changsha, Hunan Province 410013, China.
• 2Clinical Pharmacy and Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, 139# Middle Renmin Road, Changsha, Hunan Province 410011, China; School of Pharmaceutical Sciences, Central South University, 172# Tong Zipo Road, Changsha, Hunan Province 410013, China. Electronic address: yanmiaocsu@126.com.
• 3Laboratory of Cellular and Molecular Biology, Jiangsu Academy of Traditional Chinese Medicine, 100# Shizi Street, Hongshan Road, Nanjing, Jiangsu 210028, China.
• 4Clinical Pharmacy and Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, 139# Middle Renmin Road, Changsha, Hunan Province 410011, China; Laboratory of Cellular and Molecular Biology, Jiangsu Academy of Traditional Chinese Medicine, 100# Shizi Street, Hongshan Road, Nanjing, Jiangsu 210028, China. Electronic address: pcao79@yahoo.com.
• 5China Academy of Chinese Medical Sciences, Beijing 100700, China.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Licorice (Glycyrrhizae radix), the root of Glycyrrhiza uralensis Fisch. (Leguminosae), is mainly used to moderate the characteristics of toxic herbs in Traditional Chinese Medicine, which could be partly interpreted as detoxification. However, the underlying mechanism is still not fully elucidated. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the protection against toxic xenobiotics. In our previous research, we have identified that extracts from Glycyrrhiza uralensis induced the expression of Nrf2 nuclear protein and its downstream genes. This research aims to screen the most potent Nrf2 inducer isolated from Glycyrrhiza uralensis and examine its effect on Nrf2 signaling pathway and detoxification system.

MATERIALS AND METHODS:

Four compounds derived from Glycyrrhiza uralensis (glycyrrhetinic acid, liquiritigenin, isoliquiritigenin and liquiritin) were screened by ARE-luciferase reporter. The most potent ARE-luciferase inducer was chosen to further examine its effect on Nrf2 and detoxification genes in HepG2 cells. The role of Nrf2-dependent mechanism was tested by using Nrf2 knockout mice (Nrf2 KO) and Nrf2 wild-type mice (Nrf2 WT).

RESULTS:

ARE-luciferase reporter assay showed these four compounds were all potent Nrf2 inducers, and isoliquiritigenin was the most potent inducer. Isoliquiritigenin significantly up-regulated the expression of Nrf2 and its downstream detoxification genes UDP-glucuronosyltransferase 1A1 (UGT1A1), glutamate cysteine ligase (GCL), multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) in vitro and in vivo. Additionally, isoliquiritigenin showed Nrf2-dependent transactivation of UGT1A1, GCLC and MRP2.

CONCLUSIONS:

Isoliquiritigenin, isolated from Glycyrrhiza uralensis, stimulates detoxification system via Nrf2 activation, which could be a potential protective mechanism of licorice.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

Detoxification; Glycyrrhiza uralensis; Isoliquiritigenin; Licorice; Nrf2

PMID:

25557030