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

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


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.

Keywords: Detoxification; Glycyrrhiza uralensis; Isoliquiritigenin; Licorice; Nrf2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Antioxidant Response Elements
  • Chalcones / pharmacology*
  • Female
  • Flavanones / pharmacology
  • Glucosides / pharmacology
  • Glucuronosyltransferase / genetics
  • Glutamate-Cysteine Ligase / genetics
  • Glycyrrhetinic Acid / pharmacology
  • Glycyrrhiza uralensis*
  • Hep G2 Cells
  • Humans
  • Luciferases, Renilla / genetics
  • Luciferases, Renilla / metabolism
  • Mice, Inbred ICR
  • Mice, Knockout
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics
  • NF-E2-Related Factor 2 / genetics*
  • RNA, Messenger / metabolism


  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, mouse
  • Chalcones
  • Flavanones
  • Glucosides
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • isoliquiritigenin
  • Luciferases, Renilla
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • GCLM protein, mouse
  • Glutamate-Cysteine Ligase
  • Glycyrrhetinic Acid
  • liquiritin
  • liquiritigenin