基于Nrf2通路和肝脏转运体探究雷公藤甲素肝毒性及甘草配伍减毒机制
Triptolide (TP) can cause severe hepatotoxicity which limits its clinical application.Isoliquitigenin (ISL) has been reported to protect against TP-induced liver injury, but the mechanisms are not fully elucidated. This study aims to explore the role of nuclear transcription factor E2-related factor 2 (Nrf2) and hepatic transporters in TP-induced hepatotoxicity and the reversal effects of ISL on it. TP treatment caused cytotoxicity in human L02 hepatocytes and acute liver injury in ICR mice reflected by changes in liver indices, histopathology, serum biochemical indices, as well as the hepatic bile acid profiles; while combined treatment with ISL effectively alleviated TP-induced hepatotoxicity.Further, compared with the TP-injured group, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations as well as expressions of its downstream NAD(P)H:quinine oxidoreductase 1 (NQO1); expressions of hepatic transporters P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), bile salt export pump (Bsep), and organic anion transporting polypeptide (Oatp) were also induced. In addition, vesicular transport assays identified that neither was TP exported by MRP2, nor did TP influence the transport activities of P-gp and MRP2; and uptake assays showed that TP was also not a substrate of both OATP1B1 and OATP1B3. Overall, these results indicate that ISL may reduce the hepatic oxidative stress and accumulations of both endogenous bile acids and exogenous TP and its metabolites by enhancing expressions of Nrf2 and NQO1 as ell as hepatic influx and efflux transporters. Since TP does not influence the transport activities of P-gp and MRP2 and is not transported by MRP2, OATP1B1, and OATP1B3, effects of TP on hepatic transporters are mainly at transcriptional levels, and changes of hepatic bile acid profiles may be of great significance in the mechanisms of TP-induced hepatotoxicity.
雷公藤甲素 肝毒性 甘草配伍 减毒机制 肝脏转运体
侯振彦 方平飞 陈磊 蔡骅琳 汤淮波 邓阳 曹玲娟 颜苗 张毕奎
中南大学湘雅二医院药学部,湖南 长沙 410011;中南大学临床药学研究所,湖南 长沙 410011 中南大学湘雅二医院药学部,湖南 长沙 410011;中南大学临床药学研究所,湖南 长沙 410011;中南大学湘雅药学院,湖南 长沙 410013 湘潭大学化学学院,湖南 湘潭 411105 湖南中医药大学药学院,湖南 长沙 410028
国内会议
西安
中文
331-343
2017-11-04（万方平台首次上网日期，不代表论文的发表时间）