Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Beijing Union-Genius Pharmaceutical Technology Co., Ltd., Beijing 100176, China.
Molecules. 2022 Apr 20;27(9):2647. doi: 10.3390/molecules27092647.
Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the metabolic hepatotoxicity of FRA and to explore the underlying molecular mechanisms. The results showed that FRA (10-30 μM) induced liver injury and obvious alterations in the metabolomics of zebrafish larvae. FRA induces apoptosis by increasing the level of ROS and activating the JNK/P53 pathway. In addition, FRA can induce cholestasis by down-regulating bile acid transporters P-gp, Bsep, and Ntcp. The addition of the CYP3A inhibitor ketoconazole (1 μM) significantly reduced the hepatotoxicity of FRA (30 μM), which indicated that FRA induced hepatotoxicity through CYP3A metabolism. Targeted metabolomics analysis indicates the changes in amino acid levels can be combined with molecular biology to clarify the mechanism of hepatotoxicity induced by FRA, and amino acid metabolism monitoring may provide a new method for the prevention and treatment of DILI from FRA.
水黄皮素（FRA）是水黄皮中的主要活性成分，通过 CYP450 代谢呋喃环产生肝毒性。然而，FRA 肝毒性的机制尚不清楚。因此，本研究采用受精后 72 小时的斑马鱼幼鱼来评估 FRA 的代谢性肝毒性，并探讨其潜在的分子机制。结果表明，FRA（10-30 μM）诱导了斑马鱼幼鱼的肝损伤和明显的代谢组学改变。FRA 通过增加 ROS 水平和激活 JNK/P53 通路诱导细胞凋亡。此外，FRA 还可以通过下调胆汁酸转运蛋白 P-gp、Bsep 和 Ntcp 诱导胆汁淤积。添加 CYP3A 抑制剂酮康唑（1 μM）可显著降低 FRA（30 μM）的肝毒性，表明 FRA 通过 CYP3A 代谢诱导肝毒性。靶向代谢组学分析表明，氨基酸水平的变化可以结合分子生物学来阐明 FRA 诱导的肝毒性机制，并且氨基酸代谢监测可能为预防和治疗 FRA 引起的 DILI 提供新方法。
