吴茱萸肝毒性机制的阐明——基于QSAR毒性预测和代谢组学研究  

Elucidating the mechanism of hepatotoxicity in Euodia rutaecarpa:insights from QSAR toxicity prediction and metabolomics

作　　者：杨春启 赖成材 茹毅 沈宝英 吴香军 崔佳露 李方杨 张程 师卓 钱庆元 肖成荣 王宇光 张伯礼 高月 Chunqi Yang;Chengcai Lai;Yi Ru;Baoying Shen;Xiangjun Wu;Jialu Cui;Fangyang Li;Cheng Zhang;Zhuo Shi;Qingyuan Qian;Chengrong Xiao;Yuguang Wang;Boli Zhang;Yue Gao(College of Life Science and Bioengineering,Beijing University of Technology,Beijing,China;Department of Pharmaceutical Sciences,Beijing Institute of Radiation Medicine,Beijing,China;School of Pharmacy,Henan University,Kaifeng,China;State Key Laboratory of Component-based Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin,China)

机构地区：[1]北京工业大学环境与生命学部,北京 [2]军事医学研究院辐射医学研究所,北京 [3]天津中医药大学,组分中药国家重点实验室,天津 [4]不详

出　　处：《Acupuncture and Herbal Medicine》2024年第2期257-270,I0013,I0014,共16页针灸和草药（英文）

基　　金：supported by Major Program of National Natural Science Foundation of China (82192910);the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202009 and ZYYCXTD-D-202207)。

摘　　要：[目的]吴茱萸是临床上治疗胃肠道疾病的中药,已被广泛应用。然而,吴茱萸在《中国药典》及本草著作中被认为是一种“小毒”的中药。本研究采用毒性预测与体内外研究相结合的方法,鉴定吴茱萸的毒性成分和毒性靶器官,并从代谢角度探讨其毒性机制。[方法]通过体外和体内研究,对吴茱萸的毒性靶器官进行鉴定。通过生物碱富集和分离进行体外毒性筛选。基于定量构效关系(QSAR)构建,通过吸收、分布、代谢、排泄和毒性预测因子(ADMET Prodictor)预测化合物的潜在毒性。此外,研究整合了服用潜在毒性成分后的血清代谢组学分析,以阐明潜在毒性物质对小鼠代谢的影响。[结果]比较不同提取方法及炮制前后对小鼠的急性毒性,吴茱萸醇提物毒性最高,吴茱萸毒性的靶器官为肝脏。吴茱萸醇提物的生物碱组分具有较强的细胞毒性。ADMET Predictor对吴茱萸的潜在毒性进行了计算和预测,认为生物碱是导致吴茱萸毒性的主要原因。而吴茱萸碱在体外显著减少细胞数量,提高线粒体膜电位。吴茱萸碱给药后,小鼠血清代谢组学对不同的代谢产物进行了显著鉴定,其中胆汁酸代谢和类固醇激素生物合成是肝毒性的关键途径。[结论]通过比较不同提取方法在加工前后的急性毒性,阐明吴茱萸炮制品临床应用的科学意义。将基于QSAR的毒性预测与体内外毒性筛选相结合,可以鉴定吴茱萸的潜在毒性靶器官和毒性成分。通过代谢组学研究,初步揭示吴茱萸的肝毒性可能与胆汁酸代谢和类固醇激素生物合成有关。本研究为阐明吴茱萸的作用机理、评价其安全性和质量奠定了基础。Objective:Euodia rutaecarpa,(Wu Zhu Yu)a Chinese medicine clinically used to treat gastrointestinal disorders,has been widely employed.However,Euodia rutaecarpa is regarded as a small toxic traditional Chinese medicine in the Chinese Pharmacopoeia and other herbal works.Using toxicity predictions combined with in vitro and in vivo studies,this study aimed to identify the toxic components and toxic target organs of Euodia rutaecarpa,and explore its toxic mechanism from a metabolic perspective.Methods:The toxic target organs of Euodia rutaecarpa were identified through in vitro and in vivo studies.In vitro toxicity screening was performed by alkaloid enrichment and isolation.The potential toxicity of compounds was predicted by Absorption,Distribution,Metabolism,Excretion,and Toxicity Predictor(ADMET Predictor)based on Quantitative Structure–Activity Relationship(QSAR)construction.In addition,the study integrated the serum metabolomic analysis after the administration of potentially toxic components to clarify the effect of potentially toxic substances on metabolism in mice.Results:Comparing the acute toxicity in mice of different extraction methods and before and after processing,it was evident that Euodia rutaecarpa alcoholic extract had the highest toxicity,and the target organ of Euodia rutaecarpa toxicity was the liver.The alkaloid fraction of alcoholic extract of Euodia showed strong cytotoxicity.The potential toxicity of Euodia rutaecarpa was calculated and predicted by ADMET Predictor,and alkaloids are suspected to be responsible for the toxicity of Euodia rutaecarpa.Evodiamine significantly reduced the number of cells and increased the mitochondrial membrane potential in vitro.Different metabolites were significantly identified by serum metabolomics,of which bile acid metabolism and steroid hormone biosynthesis are the key pathways of hepatotoxicity.Conclusions:Clarify the scientific significance of clinical use of processed products by comparing the acute toxicity of different extraction methods before a

关 键 词：ADMET Prodictor 吴茱萸 吴茱萸碱 肝毒性 LD50 代谢组学 

分 类 号：R285.1[医药卫生—中药学]