Effect Of Licorice On The Nrf2/ARE Signal Pathway And Its Downstream Detoxification-related Genes

Objectives:Investigate the effects of licorice on the expression of Nrf2and its downstream phase â…¡ detoxifying enzymes UGT1A1, yGCS/GCLC and drug transporters MRP2, BSEP.Methods:Firstly, study the effects of licorice extracts on the expression of Nrf2protein and UGT1A1, yGCS/GCLC, MRP2and BSEP mRNA. Secondly, four kinds of licorice-derived compounds (glycyrrhetinic acid, liguiritigenin, isoliquiritigenin and liquiritin) were screened by ARE-luciferase reporter. Thirdly, the effect of the most potent ARE-luciferase inducer on the expression of Nrf2and its downstream detoxification-related genes was examined in HepG2cells. Additionally, the role of Nrf2in licorice-mediated gene expression was tested by using Nrf2knockout miceand Nrf2wild-type mice.Results:Licorice extract significantly induced the mRNA expression of phase â…¡ UGT1A1, GCL, MRP2, as well as the protein expression of Nrf2. Then, isoliquiritigenin was the most potent ARE-luciferase inducer. Isoliquiritigenin significantly up-regulated the expression of Nrf2and UGT1A1, GCLC, MRP2, BSEP in vitro and in vivo. Additionally, isoliquiritigenin showed Nrf2-dependent transactivation of UGT1A1, GCLC and MRP2.Conclusions:These findings suggest that licorice may intervene in Nrf2signal pathway to induce UGT1A1, GCLC, MRP2and BSEP, which provide a novel mechanism for the use of licorice to treat drug poisoning and/or relieve adverse effects.