药物引起的肝损伤是全世界关注的健康问题，药源性肝损伤的早期诊断仍然是临床治疗肝损伤的一大难题。本研究中，首先利用对乙酰氨基酚、四氯化碳、大黄素、雷公藤甲素和马兜铃酸构建不同类型的肝细胞损伤模型，利用超高效液相色谱-质谱联用技术（ UPLC-MS）分别得到正常组和损伤组的细胞代谢轮廓谱。然后利用模式识别构建分类模型，筛选肝损伤相关的差异代谢物。结果显示，不同类型肝损伤在肝细胞代谢谱上可以被区分开，最终鉴定出14种差异代谢物。损伤组肝细胞经保肝阳性药联苯双酯干预后，差异代谢物水平均趋向于正常组，在一定程度上验证了差异标志物与肝损伤的相关性。实验结果表明细胞代谢组学是研究药物肝损伤的有效工具之一。
Drug-induced hepatotoxicity is a worldwide health issue. And diagnosing the injury in the early stage is still a challenge in clinic. In this study,pattern recognition analysis of the ultra high performance liquid chromatography-mass spectrometry( UPLC-MS)of hepatocytes HL7702 was performed to develop differential metabolites related to hepatotoxicity induced by hepatotoxicants,including carbon tetrachloride(CCl4),acetaminophen(APAP),emodin, aristolochic acid( AA)and triptolide. Hepatocytes injuries were induced by 48 h of treatment with CCl4(4 mmol/L),APAP(6. 5 mmol/L),emodin(14 μmol/L),AA(35 μmol/L)and trip-tolide(18 nmol/L),separately. Global metabolomics profiling,multivariate analysis and data-base searching were performed to discover common differential metabolites for live injury. The positive hepatoprotective drug,bifendate,was used to repair triptolide induced hepatocytes in-jury,and bifendate-induced changes of hepatotoxicity-related metabolites were investigated. In the results,fatty acid oxidation and cellular oxidative stress-related metabolites,including nico-tinamide adenine dinucleotide and glutathione were significantly changed between the control and hepatotoxicant-treated groups,and after treatment with bifendate,those perturbed metab-olites all partly returned to normal level. In conclusion,we discovered potential hepatotoxicity-related metabolites that could be used to evaluate hepatotoxicity induced by chemicals,drugs and traditional Chinese medicines. This study also proved that metabolomics is one of the effec-tive tools to investigate drug-induced hepatotoxicity.
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