Peng Wan, Dai Man-Yun, Bao Li-Juan, Zhu Wei-Feng, Li Fei
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
University of Chinese Academy of Sciences, Beijing, China.
Xenobiotica. 2021 Jun;51(6):716-727. doi: 10.1080/00498254.2021.1900626. Epub 2021 Mar 30.
Tripterygium glycosides tablets (TGT) and tablets (TWT) are the preparations of used to treat rheumatoid arthritis (RA) in the clinic, but the hepatotoxicity was reported frequently. This study aimed to determine the potential toxicity mechanism of liver injury induced by the preparations of in mice.Here, we performed metabolomic analysis, pathological analysis and biochemical analysis of samples from mice with liver injury induced by TGT and TWT, which revealed that liver injury was associated with bile acid metabolism disorder. Quantitative real-time PCR (QPCR) and western blot indicated that the above changes were accompanied by inhibition of farnesoid X receptor (FXR) signalling.Liver injury from TWT could be alleviated by treatment of the FXR agonist obeticholic acid (OCA) via activation of the FXR to inhibit the c-Jun N-terminal kinase (JNK) pathway and improve bile acid metabolism disorder by activating bile salt export pump (BSEP) and organic solute-transporter-β (OSTB). The data demonstrate that FXR signalling pathway plays a key role in -induced liver injury, which could be alleviated by activated FXR.These results indicate that FXR activation by OCA may offer a promising therapeutic opportunity against hepatotoxicity from the preparations of .
雷公藤多苷片（TGT）和 片（TWT）是临床上用于治疗类风湿性关节炎（RA）的制剂，但肝毒性报道频繁。本研究旨在确定 制剂诱导小鼠肝损伤的潜在毒性机制。在此，我们对TGT和TWT诱导肝损伤小鼠的样本进行了代谢组学分析、病理分析和生化分析，结果显示肝损伤与胆汁酸代谢紊乱有关。定量实时PCR（QPCR）和蛋白质印迹表明上述变化伴随着法尼酯X受体（FXR）信号传导的抑制。通过激活FXR抑制c-Jun氨基末端激酶（JNK）途径，并通过激活胆盐输出泵（BSEP）和有机溶质转运体-β（OSTB）改善胆汁酸代谢紊乱，FXR激动剂奥贝胆酸（OCA）治疗可减轻TWT所致的肝损伤。数据表明FXR信号通路在 诱导的肝损伤中起关键作用，激活FXR可减轻肝损伤。这些结果表明，OCA激活FXR可能为对抗 制剂所致肝毒性提供一个有前景的治疗机会。
