Abstract
Triptolide (TP), the main bioactive component of Tripterygium wilfordii Hook F, can cause severe hepatotoxicity. Isoliquiritigenin (ISL) has been reported to be able 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 protective effect of ISL. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to the disorder of bile acid (BA) profiles in mice livers. Combined treatment of TP with ISL effectively alleviated TP-induced hepatotoxicity. Furthermore, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NAD(P)H: quinine oxidoreductase 1 (NQO1) expression. Expressions of hepatic P-gp, MRP2, MRP4, bile salt export pump, 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. All these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous BAs and exogenous TP as well as its metabolites by enhancing the expressions of Nrf2, NQO1, and hepatic influx and efflux transporters. Effects of TP on hepatic transporters are mainly at the transcriptional levels, and changes of hepatic BA profiles are very important in the mechanisms of TP-induced hepatotoxicity.
Highlights
Triptolide, the main bioactive component of the traditional Chinese herb Tripterygium wilfordii Hook F (TwHF), possesses various pharmacological properties (Wang et al, 2004; Liu, 2011; Li X. et al, 2014)
bile acid (BA) were as follows: cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), hyodeoxycholic acid (HDCA), taurochemodeoxycholic acid (TCDCA), and tauroursodeoxycholic acid (TUDCA) were from On-Road Biotechnology Co., Ltd. (Changsha, China); lithocholic acid (LCA), taurocholic acid (TCA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA), taurohyodeoxycholic acid (THDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), glycochenodeoxycholic acid (GCDCA), and glycoursodeoxycholic acid (GUDCA) were from Sigma-Aldrich
TP 50 nM was used in subsequent experiments, which was close to the half maximal inhibitory concentration (IC50)
Summary
Triptolide, the main bioactive component of the traditional Chinese herb TwHF, possesses various pharmacological properties (Wang et al, 2004; Liu, 2011; Li X. et al, 2014). With regard to the mechanisms of TP-induced hepatotoxicity, previous studies have indicated that oxidative stress damage induced by TP is important (Wang J. et al, 2013), which is shown by increased ROS levels and decreased content of GSH in the liver (Li J. et al, 2014; Li X. et al, 2014). Since TP-induced hepatotoxicity is quantitatively correlated with the hepatic exposure to the parent drug, changes in pharmacokinetic profiles of TP may influence its hepatotoxicity (Kong et al, 2015), and CYP3A-mediated metabolism of TP is a detoxification pathway (Xue et al, 2011). Combined with the cholestatic symptoms of TP administration observed in clinics (Xue et al, 2009), we speculate that besides the hepatic accumulation of TP, mechanisms involved in the change of endogenous BA profiles may as well contribute to TP-induced hepatotoxicity
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