title: A protective mechanism of licorice (Glycyrrhiza uralensis): isoliquiritigenin stimulates detoxification system via Nrf2 activation.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Clinical 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.affiliation: Clinical 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.
authors.forename: Bi-kui
authors.initials: BK
authors.lastname: Zhang
authors.affiliation: Clinical 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.
authors.forename: Miao
authors.initials: M
authors.lastname: Yan
authors.affiliation: Clinical 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.
authors.forename: Ping-fei
authors.initials: PF
authors.lastname: Fang
authors.affiliation: Clinical 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.
authors.forename: Huan-de
authors.initials: HD
authors.lastname: Li
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Academy of Traditional Chinese Medicine, 100# Shizi Street, Hongshan Road, Nanjing, Jiangsu 210028, China.
authors.forename: Chun-ping
authors.initials: CP
authors.lastname: Hu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Academy of Traditional Chinese Medicine, 100# Shizi Street, Hongshan Road, Nanjing, Jiangsu 210028, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Clinical 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: Clinical 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.
authors.forename: Pei
authors.initials: P
authors.lastname: Jiang
authors.affiliation: China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Xin-rong
authors.initials: XR
authors.lastname: Fan
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D061745:Antioxidant Response Elements; D047188:Chalcones / Q000494:pharmacology*; D005260:Female; D044950:Flavanones / Q000494:pharmacology; D005960:Glucosides / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000235:genetics; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D029882:Glycyrrhiza uralensis; D056945:Hep G2 Cells; D006801:Humans; D049410:Luciferases, Renilla / Q000235:genetics / Q000378:metabolism; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D047188:Chalcones; D044950:Flavanones; D005960:Glucosides; D014453:Glucuronosyltransferase; D005721:Glutamate-Cysteine Ligase; D006034:Glycyrrhetinic Acid; D049410:Luciferases, Renilla; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C490549:Abcb11 protein, mouse; C495636:Nfe2l2 protein, mouse; C040920:isoliquiritigenin; C560749:GCLM protein, mouse; C512196:liquiritin; C083152:liquiritigenin
keywords: Detoxification; Glycyrrhiza uralensis; Isoliquiritigenin; Licorice; Nrf2