基于非靶向代谢组学的白鲜碱致肝损伤性别差异研究  

Difference in liver injury induced by dictamnine between males and females:based on untargeted metabolomics

作　　者：涂灿 郭兆娟 蒋冰倩 康倩君 王停[1] TU Can;GUO Zhao-juan;JIANG Bing-qian;KANG Qian-jun;WANG Ting(National Medical Products Administration Key Laboratory for Research and Evaluation of Traditional Chinese Medicine,Beijing International Science and Technology Cooperation Base for Traditional Chinese Medicine Hepatotoxicity and New Drug Research and Development,Beijing Research Institute of Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]北京中医药大学、北京中医药研究院、国家药品监督管理局中医药研究与评价重点实验室、北京市中药肝损伤与新药研发国际科技合作基地,北京100029

出　　处：《中国中药杂志》2023年第12期3317-3326,共10页China Journal of Chinese Materia Medica

基　　金：北京中医药大学新教师启动基金项目(2022-JYB-XJSJJ-024);国家自然科学基金青年基金项目(82104522)。

摘　　要：近年来,中药相关不良反应报道逐渐增多,特别是一些传统上认为“无毒”中药材(如白鲜皮)却引起严重不良反应,使得中药安全性问题备受关注。该研究旨在通过4周小鼠毒性动物实验证实白鲜碱致肝损伤性别差异的客观性,采用血清非靶向代谢组学方法阐明白鲜碱致肝损伤性别差异作用及代谢网络调控机制。结果显示在雌性小鼠中,白鲜碱导致血清肝功能生化指标和脏器系数显著升高(P<0.05),肝脏组织病理学观察肝细胞泡状脂肪变性为主;在雄性小鼠中,白鲜碱组未观察到肝组织病理学改变。进一步采用非靶向代谢组学研究,通过多元统计分析筛选出白鲜碱致肝损伤性别差异的代谢产物48个(如色氨酸、皮质甾酮、可的松及吲哚等),采用受试者工作特征曲线(receiver operating characteristic curve, ROC曲线)综合聚类分析,筛选出14个指纹代谢标志物与白鲜碱致肝损伤性别差异高度相关,最后通路富集分析提示色氨酸代谢、甾类激素生物合成、铁死亡(亚油酸代谢、花生四烯酸代谢)等代谢通路紊乱与白鲜碱致肝损伤性别差异密切相关。白鲜碱致肝损伤可导致显著性别差异,色氨酸代谢、甾类激素生物合成、铁死亡等代谢通路紊乱可能是白鲜碱致肝损伤性别差异的潜在作用机制。In recent years,reports of adverse reactions related to traditional Chinese medicine(TCM)have been on the rise,especially some traditionally considered"non-toxic"TCM(such as Dictamni Cortex).This has aroused the concern of scholars.This study aims to explore the metabolomic mechanism underlying the difference in liver injury induced by dictamnine between males and females through the experiment on 4-week-old mice.The results showed that the serum biochemical indexes of liver function and organ coefficients were significantly increased by dictamnine(P<0.05),and hepatic alveolar steatosis was mainly observed in female mice.However,no histopathological changes were observed in the male mice.Furthermore,a total of 48 differential metabolites(such as tryptophan,corticosterone,and indole)related to the difference in liver injury between males and females were screened out by untargeted metabolomics and multivariate statistical analysis.According to the receiver operating characteristic(ROC)curve,14 metabolites were highly correlated with the difference.Finally,pathway enrichment analysis indicated that disorders of metabolic pathways,such as tryptophan metabolism,steroid hormone biosynthesis,and ferroptosis(linoleic acid metabolism and arachidonic acid metabolism),may be the potential mechanism of the difference.Liver injury induced by dictamnine is significantly different between males and females,which may be caused by the disorders of tryptophan metabolism,steroid hormone biosynthesis,and feroptosis pathways.

关 键 词：肝损伤 白鲜碱 性别差异 非靶向代谢组学 机制 

分 类 号：R285[医药卫生—中药学]