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.
Biomed Chromatogr. 2020 Aug;34(8):e4864. doi: 10.1002/bmc.4864. Epub 2020 Jun 18.
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.
雷公藤红素（TP）是中草药雷公藤中的主要生物活性二萜类化合物之一，临床上用于治疗自身免疫性疾病，但同时伴有严重的肝毒性。已有报道称 CYP3A4 负责 TP 的代谢，但具体机制尚不清楚。本研究应用基于 UPLC-QTOF-MS 的代谢组学分析方法，研究 CYP3A4 对 TP 诱导的肝毒性的影响。在 TP 处理的雌性小鼠中，发现肉碱、溶血磷脂酰胆碱（LPC）和一系列氨基酸与肝损伤指标密切相关。代谢组学分析进一步表明，CYP3A4 诱导剂地塞米松可改善 LPC 和氨基酸水平，抵御氧化应激。相反，用 CYP3A4 抑制剂酮康唑预处理会增加肝损伤，大多数代谢物明显改变，尤其是肉碱。在这些代谢物中，除 LPC18:2、LPC20:1 和精氨酸外，地塞米松和酮康唑均影响 TP 诱导的氧化应激。本研究为代谢物改变的机制提供了新的见解，有助于了解 CYP3A4 在 TP 诱导的肝毒性中的作用。
