摘要
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＆nbsp;and traditional Chinese medicines. This study also proved that metabolomics is one of the effec-tive tools to investigate drug-induced hepatotoxicity.
出处
《色谱》
CAS
CSCD
北大核心
2015年第7期683-690,共8页
Chinese Journal of Chromatography
基金
国家科技重大专项(2014ZX09304307-001-006)
关键词
超高效液相色谱-质谱
代谢组学
肝损伤
ultra high performance liquid chromatography-mass spectrometry （ UPLC-MS ）
metabolomics
hepatotoxicity
