State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
J Pharm Biomed Anal. 2018 Oct 25;160:404-414. doi: 10.1016/j.jpba.2018.08.018. Epub 2018 Aug 10.
Triptolide (TP) is the crucial active ingredient of Tripterygium glycoside tablets and has been shown to have a significant therapeutic effect on delayed-type hypersensitivity (DTH)-related diseases. However, due to its potential hepatotoxicity and nephrotoxicity, adverse reactions have often been observed in long-term treatment regimens. Therefore, it is meaningful to find metabolic markers for toxicity for early diagnosis. In this study, a feasible strategy using HPLC-HRMS method combined with multivariate statistical analysis to discover toxic potential markers of TP was developed. TP was used to treat a DTH mouse model at a therapeutic dose (45μg/kg) and toxic dose (900 μg/kg). The metabolic profiles of the liver, kidney and plasma were characterized by HPLC-Q/TOF MS. Significant differences in the metabolite profiles of the liver, kidney and plasma existed between the toxic and therapeutically dosed mice. Forty-six metabolites were identified and 27 of them may be related to toxicity based on a structure-toxicity prediction model. Using OPLS-DA analysis, the metabolite profiles between the two dose groups could be well distinguished. It was found that 18, 4 and 4 metabolic markers were altered in the liver, kidney and plasma, respectively; 15, 4 and 3 of these metabolic markers were predicted to be toxic. Two toxic markers detected both in mouse plasma and human liver microsomes following incubation with TP showed great potential as early diagnosis markers for TP hepatotoxicity and nephrotoxicity.
雷公藤红素（TP）是雷公藤苷片的主要活性成分，已被证明对迟发型超敏反应（DTH）相关疾病具有显著的治疗作用。然而，由于其潜在的肝毒性和肾毒性，长期治疗方案中经常观察到不良反应。因此，寻找毒性代谢标志物进行早期诊断具有重要意义。在这项研究中，开发了一种使用 HPLC-HRMS 方法结合多变量统计分析来发现 TP 毒性潜在标志物的可行策略。用治疗剂量（45μg/kg）和毒性剂量（900μg/kg）的 TP 治疗 DTH 小鼠模型。通过 HPLC-Q/TOF MS 对肝、肾和血浆的代谢谱进行了特征描述。在毒性和治疗剂量的小鼠之间，肝、肾和血浆的代谢谱存在显著差异。鉴定出 46 种代谢物，其中 27 种可能基于结构-毒性预测模型与毒性有关。使用 OPLS-DA 分析，可很好地区分两组剂量之间的代谢谱。结果发现，肝脏、肾脏和血浆中分别有 18、4 和 4 种代谢标志物发生变化；其中 15、4 和 3 种代谢标志物被预测为有毒性。在与 TP 孵育后，从小鼠血浆和人肝微粒体中检测到的两种毒性标志物都显示出作为 TP 肝毒性和肾毒性早期诊断标志物的巨大潜力。
