Gong Hui, Zhang Bi-kui, Yan Miao, Fang Ping-fei, Li Huan-de, Hu Chun-ping, Yang Yang, Cao Peng, Jiang Pei, Fan Xin-rong
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.
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.
J Ethnopharmacol. 2015 Mar 13;162:134-9. doi: 10.1016/j.jep.2014.12.043. Epub 2014 Dec 31.
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.
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).
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.
Isoliquiritigenin, isolated from Glycyrrhiza uralensis, stimulates detoxification system via Nrf2 activation, which could be a potential protective mechanism of licorice.
甘草（甘草根），即乌拉尔甘草（豆科）的根，在传统中药中主要用于缓和有毒草药的特性，这在一定程度上可解释为解毒作用。然而，其潜在机制仍未完全阐明。核因子红细胞2相关因子2（Nrf2）在抵御有毒外源性物质中起关键作用。在我们之前的研究中，我们已确定乌拉尔甘草提取物可诱导Nrf2核蛋白及其下游基因的表达。本研究旨在筛选从乌拉尔甘草中分离出的最有效的Nrf2诱导剂，并研究其对Nrf2信号通路和解毒系统的影响。
通过ARE-荧光素酶报告基因筛选从乌拉尔甘草中提取的四种化合物（甘草次酸、甘草素、异甘草素和甘草苷）。选择最有效的ARE-荧光素酶诱导剂进一步研究其对HepG2细胞中Nrf2和解毒基因的影响。使用Nrf2基因敲除小鼠（Nrf2 KO）和Nrf2野生型小鼠（Nrf2 WT）来测试Nrf2依赖性机制的作用。
ARE-荧光素酶报告基因检测表明这四种化合物均为有效的Nrf2诱导剂，异甘草素是最有效的诱导剂。异甘草素在体外和体内均显著上调Nrf2及其下游解毒基因尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1）、谷氨酸半胱氨酸连接酶（GCL）、多药耐药蛋白2（MRP2）和胆盐输出泵（BSEP）的表达。此外，异甘草素显示出对UGT1A1、GCLC和MRP2的Nrf2依赖性反式激活作用。
从乌拉尔甘草中分离出的异甘草素通过激活Nrf2刺激解毒系统，这可能是甘草的一种潜在保护机制。
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