AUTHOR=Hou Zhenyan , Chen Lei , Fang Pingfei , Cai Hualin , Tang Huaibo , Peng Yongbo , Deng Yang , Cao Lingjuan , Li Huande , Zhang Bikui , Yan Miao 

TITLE=Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00226

DOI=10.3389/fphar.2018.00226

ISSN=1663-9812

ABSTRACT=Triptolide (TP), the main bioactive component of Tripterygium wilfordii Hook F, can cause severe hepatotoxicity. 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 effect of ISL on it. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to a disorder of bile acid profiles in mice livers. Combined treatment with ISL effectively alleviated TP-induced hepatotoxicity. Further, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NQO1 expressions; expressions of hepatic P-gp, MRP2, MRP4, BSEP, and Oatp2 were also induced. In addition, in vitro transport assays identified that neither was TP exported by MRP2, OATP1B1 or OATP1B3, nor did TP influence the transport activities of P-gp or MRP2. Overall, these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous bile acids and exogenous TP and its metabolites by enhancing expressions of Nrf2, NQO1 and hepatic influx and efflux transporters. 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.