目的考察前期發(fā)現(xiàn)的腎毒性小分子代謝標(biāo)志物在中藥毒性評價中的適用性。方法以已知具有腎毒性的5種中藥雷公藤、馬錢子、廣防己、大黃和蒼耳子提取液ig給予大鼠建立腎臟損傷模型,收集給藥1和7 d后的血樣,應(yīng)用超高效液相色譜-質(zhì)譜聯(lián)用（UPLC/Q-TOF-MS）檢測5種腎毒性生物標(biāo)志物胸苷、溶血磷脂酰膽堿LPC（16：1）、LPC（18：4）、LPC（20：5）和LPC（22：5）水平,建立支持向量機（SVM）預(yù)測模型對其毒性進(jìn)行判斷；全自動生化儀測定血清中Cr和BUN的水平；各組大鼠于取血后處死,迅速取腎臟進(jìn)行HE染色,光學(xué)顯微鏡下觀察病理表現(xiàn)。結(jié)果對照組沒有表現(xiàn)出毒性。5種中藥在給藥1 d后,生化檢測沒有發(fā)現(xiàn)腎臟損傷,腎毒性支持向量機預(yù)測模型發(fā)現(xiàn)異常；在給藥7天后,SVM的預(yù)測結(jié)果與生化和病理檢測結(jié)果一致,均出現(xiàn)腎毒性。結(jié)論代謝組學(xué)技術(shù)結(jié)合支持向量機模型可將腎毒性小分子代謝物更加靈敏、快速、準(zhǔn)確地用于中藥腎臟毒性評價,對于臨床藥源性腎損傷的防治具有重要意義。

Objective To evaluate the applicability of small molecular markers of nephrotoxicity that in prediction of drug toxicity. Method Extracts of five kinds of traditional Chinese medicines (Tripterygium wilfordii,Strychni semen,Aristolochia fangchi,Rhei Radix et Rhizoma,and Xanthium sibiricum) that had known as nephrotoxicity were ig given to rats to establish renal injury models, and the blood samples were collected after administration for 1 and 7 d.Then blood samples were analyzed by UPLC/Q-TOF-MS for five kinds of small molecule biomarkers——thymidine,lyso-phosphatidylcholine (LPC 16:1),LPC (18:4),LPC (20:5),and LPC (22:5).The support vector machine (SVM) prediction model was established to determine the toxicity.The levels of Cr and BUN in serum were determined by automatic biochemical analyzer.The rats in each group were sacrificed after blood collection,and the kidneys were taken for HE staining.Result No toxicity was observed in the control group,and the biochemical test results showed no renal injury after mentioned five kinds Chinese herbs were given for 1 d,while SVM model of nephrotoxicity had been found abnormal.After administration for 7 d,the results of SVM model show renal toxicity,which were consistent with biochemical and pathological examination.Conclusion Metabonomics combined with the earlier established SVM model enabled prediction of drug nephrotoxicity more sensitively,quickly and accurately,and it is of great significance for the discovery of drug toxicity as well as the prevention and treatment of drug-induced renal injuries in clinic.

國家科技支撐計劃課題（2011BAI07B08）；國家自然科學(xué)基金資助項目（81573835）