Strategy for Hepatotoxicity Prediction Induced by Drug Reactive Metabolites Using Human Liver Microsome and Online 2D-Nano-LC-MS Analysis
文献类型：期刊论文
| 作者 | Zhuo, Yue2; Wu, Jian-Lin2; Yan, Xiaojing2,4; Guo, Ming-Quan3; Liu, Ning1; Zhou, Hua2; Liu, Liang2; Li, Na2 |
| 刊名 | ANALYTICAL CHEMISTRY
 |
| 出版日期 | 2017-12-19 |
| 卷号 | 89期号:24页码:13167-13175 |
| ISSN号 | 0003-2700 |
| DOI | 10.1021/acs.analchem.7b02684 |
| 英文摘要 | Hepatotoxicity is a leading cause of drug withdrawal from the market; thus, the assessment of potential drug induced liver injury (DILI) in preclinical trials is necessary. More and more research has shown that the covalent modification of drug reactive metabolites (RMs) for cellular proteins is a possible reason for DILI. Unfortunately, so far no appropriate method can be employed to evaluate this kind of DILI due to the low abundance of RM-protein adducts in complex biological samples. In this study, we proposed a mechanism-based strategy to solve this problem using human liver microsomes (HLMs) and online 2D nano-LC-MS analysis. First, RM modification patterns and potential modified AA residues are determined using HLM and model amino acids (AAs) by UHPLC-QTOF-MS. Then, a new online 2D-nano-LC-Q-TOF-MS method is established and applied to separate the digested modified microsomal peptides from high abundance peptides followed by identification of RM-modified proteins using Mascot, in which RM modification patterns on specific AA residues are added. Finally, the functions and relationship with hepatotoxicity of the RM-modified proteins are investigated using ingenuity pathway analysis (IPA) to predict the possible DILI. Using this strategy, 21 proteins were found to be modified by RMs of toosendanin, a hepatotoxic drug with complex structure, and some of them have been reported to be associated with hepatotoxicity. This strategy emphasizes the identification of drug RM-modified proteins in complex biological samples, and no pretreatment is required for the drugs. Consequently, it may serve as a valuable method to predict potential DILI, especially for complex compounds. |
| 资助项目 | Macao Science and Technology Development Fund[003/2016/A1] ; National Natural Sciences Foundation of China[81603296] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000418626300019 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://202.127.146.157/handle/2RYDP1HH/1270]  |
| 专题 | 中国科学院武汉植物园 |
| 通讯作者 | Liu, Liang; Li, Na |
| 作者单位 | 1.Jilin Univ, Hosp 2, Cent Lab, Changchun, Jilin, Peoples R China 2.Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Ave Wai Long, Taipa, Macao, Peoples R China 3.Chinese Acad Sci, Sinoafrica Joint Res Ctr, Wuhan Bot Garden, Key Lab Plant Germplasm Enhancement & Specialty A, Wuhan 430074, Hubei, Peoples R China 4.Nanjing Univ Chinese Med, Changzhou Affiliated Hosp, 25 Heping North Rd, Changzhou 213003, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhuo, Yue,Wu, Jian-Lin,Yan, Xiaojing,et al. Strategy for Hepatotoxicity Prediction Induced by Drug Reactive Metabolites Using Human Liver Microsome and Online 2D-Nano-LC-MS Analysis[J]. ANALYTICAL CHEMISTRY,2017,89(24):13167-13175. |
| APA | Zhuo, Yue.,Wu, Jian-Lin.,Yan, Xiaojing.,Guo, Ming-Quan.,Liu, Ning.,...&Li, Na.(2017).Strategy for Hepatotoxicity Prediction Induced by Drug Reactive Metabolites Using Human Liver Microsome and Online 2D-Nano-LC-MS Analysis.ANALYTICAL CHEMISTRY,89(24),13167-13175. |
| MLA | Zhuo, Yue,et al."Strategy for Hepatotoxicity Prediction Induced by Drug Reactive Metabolites Using Human Liver Microsome and Online 2D-Nano-LC-MS Analysis".ANALYTICAL CHEMISTRY 89.24(2017):13167-13175. |
入库方式： OAI收割
来源：武汉植物园
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