Emodin-induced hepatotoxicity was exacerbated by probenecid through inhibiting UGTs and MRP2

摘要

Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150?mg/kg) hepatotoxicity was exacerbated by probenecid (100?mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve,AUC) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increasedAUC(increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%–58.1%). In addition,AUCof emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly,in vitroexperiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2in vivoandin vitro, indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.