Triptolide (TP), one of the main bioactive diterpenes of the herbal medicine Tripterygium wilfordii Hook F, is used for the treatment of autoimmune diseases in the clinic and is accompanied by severe hepatotoxicity. CYP3A4 has been reported to be responsible for TP metabolism, but the mechanism remains unclear. The present study applied a UPLC–QTOF–MS‐based metabolomics analysis to characterize the effect of CYP3A4 on TP‐induced hepatotoxicity. The metabolites carnitines, lysophosphatidylcholines (LPCs) and a serious of amino acids were found to be closely related to liver damage indexes in TP‐treated female mice. Metabolomics analysis further revealed that the CYP3A4 inducer dexamethasone improved the level of LPCs and amino acids, and defended against oxidative stress. On the contrary, pretreatment with the CYP3A4 inhibitor ketoconazole increased liver damage with most metabolites being markedly altered, especially carnitines. Among these metabolites, except for LPC18:2, LPC20:1 and arginine, dexamethasone and ketoconazole both affected oxidative stress induced by TP. The current study provides new mechanistic insights into the metabolic alterations, leading to understanding of the role of CYP3A4 in hepatotoxicity induced by TP.

中文翻译：

---

CYP3A4对雷公藤甲素致肝损伤的影响。

雷公藤甲素（TP），草药的主要生物活性二萜的一个雷公藤钩F在临床上用于治疗自身免疫性疾病，并伴有严重的肝毒性。据报道CYP3A4是TP代谢的原因，但其机制尚不清楚。本研究应用基于UPLC–QTOF–MS的代谢组学分析来表征CYP3A4对TP诱导的肝毒性的影响。TP处理的雌性小鼠体内的代谢产物肉碱，溶血磷脂酰胆碱（LPC）和大量氨基酸与肝脏损伤指数密切相关。代谢组学分析进一步表明，CYP3A4诱导剂地塞米松可提高LPC和氨基酸的水平，并防御氧化应激。相反，用CYP3A4抑制剂酮康唑进行的预处理增加了肝脏损害，大多数代谢物（尤其是肉碱）发生了明显变化。在这些代谢产物中，除了LPC18：2，LPC20：1和精氨酸外，地塞米松和酮康唑都影响TP诱导的氧化应激。本研究为代谢改变提供了新的机制见解，从而使人们了解了CYP3A4在TP诱导的肝毒性中的作用。