基于血清代谢组学和网络毒理学研究闹羊花毒性作用机制  

Toxicity mechanism of Rhododendri Mollis Flos: based on serum metabolomics and network toxicology

作　　者：郭小红 黄孟军[3] 王立娟[2] 冉强[2] 杨森 吴文辉 张小琼 刘友平[1] GUO Xiao-hong;HUANG Meng-jun;WANG Li-juan;RAN Qiang;YANG Sen;WU Wen-hui;ZHANG Xiao-qiong;LIU You-ping(State Key Loboratory of Southwestern Chinese Medicine Resources,School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China;Chongqinp Traditional Chinese Medicine Hospital,Chongqing 400021,China;National-Local Joint Engineering Research Center for Innovative Targeted Drugs,College of Pharmaceutical Sciences,Chongqing University of Arts and Sciences,Chongqing 402160,China)

机构地区：[1]成都中医药大学药学院西南特色中药资源国家重点实验室,四川成都611137 [2]重庆市中医院,重庆400021 [3]重庆文理学院药学院创新靶向药物国家地方联合工程研究中心,重庆402160

出　　处：《中国中药杂志》2022年第7期1932-1941,共10页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(82104398);中国博士后科学基金项目(2021M700623);重庆市自然科学基金面上项目(cstc2021jcyj-msxmX0409);成都中医药大学2020年度“杏林学者”医院专项(YYZX2020049)。

摘　　要：基于血清代谢组学和网络毒理学研究有毒中药闹羊花的毒性作用机制。正常大鼠灌胃给予闹羊花药材粉末后,通过中毒症状、血清生化及病理组织学评价其毒性作用。利用血清代谢组学技术结合多元统计学分析,寻找内源性差异代谢物及相关代谢通路;采用网络毒理学技术挖掘闹羊花的毒性成分、靶点及信号通路,并进一步与血清代谢组学整合分析,筛选并构建关键“成分-靶点-代谢物-代谢通路”。血清生化和病理组织结果表明闹羊花有明显神经、肝脏、心脏毒性。血清代谢组学发现了31个差异代谢物,获取10条主要代谢通路;网络毒理学挖掘出闹羊花中11个毒性成分相关的332个靶点和141条信号通路。进一步整合分析,筛选出闹羊花中木藜芦毒素Ⅲ、木藜芦毒素Ⅰ;闹羊花毒素Ⅱ、闹羊花毒素Ⅴ、闹羊花毒素Ⅵ、闹羊花毒素Ⅶ和kalmanol 7关键毒性成分,作用于AR、ALB、ESR2、SHBG、HSD17B11、ESR1、RXRG、LDHC、AKR1C3、ABCB1、UGT2B7、GLUL 12个靶点,干扰氨基丁酸、雌三醇、睾丸素、视黄酸、2-氧丁酸5种内源性代谢物,影响丙氨酸、天冬氨酸和谷氨酸代谢,半胱氨酸和蛋氨酸、类固醇激素生物合成,视黄醇代谢4条代谢通路。可见,闹羊花毒性累及多器官系统,由多成分、多靶点、多途径所致,通过关键毒性成分、靶基因、代谢物及代谢通路,揭示了其潜在神经、心脏、肝脏毒性机制,为有毒中药基础研究提供了思路。This study aims to explore the toxicity mechanism of Rhododendri Mollis Flos(RMF) based on serum metabolomics and network toxicology. The toxic effect of RMF on normal rats was evaluated according to the symptoms, serum biochemical indexes, and histopathology. Serum metabolomics was combined with multivariate statistical analysis to search endogenous differential metabolites and related metabolic pathways. The toxic components, targets, and signaling pathways of RMF were screened by network toxicology technique, and the component-target-metabolite-metabolic pathway network was established with the help of serum metabolomics. The result suggested the neurotoxicity, hepatotoxicity, and cardiotoxicity of RMF. A total of 31 differential metabolites and 10 main metabolic pathways were identified by serum metabolomics, and 11 toxic components, 332 related target genes and 141 main signaling pathways were screened out by network toxicology. Further analysis yielded 7 key toxic components: grayanotoxin Ⅲ,grayanotoxinⅠ, rhodojaponin Ⅱ, rhodojaponin Ⅴ, rhodojaponin Ⅵ, rhodojaponin Ⅶ, and kalmanol, which acted on the following 12 key targets: androgen receptor(AR), albumin(ALB), estrogen receptor β(ESR2), sex-hormone binding globulin(SHBG), type 11 hydroxysteroid(17-beta) dehydrogenase(HSD17 B11), estrogen receptor α(ESR1), retinoic X receptor-gamma(RXRG), lactate dehydrogenase type C(LDHC), Aldo-keto reductase(AKR) 1 C family member 3(AKR1 C3), ATP binding cassette subfamily B member 1(ABCB1), UDP-glucuronosyltransferase 2 B7(UGT2 B7), and glutamate-ammonia ligase(GLUL). These targets interfered with the metabolism of gamma-aminobutyric acid, estriol, testosterone, retinoic acid, 2-oxobutyric acid, and affected 4 key metabolic pathways of alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism, steroid hormone biosynthesis, and retinol metabolism. RMF exerts toxic effect on multiple systems through multiple components, targets, and pathways. Through the analysis of key toxic components

关 键 词：闹羊花 代谢组学 生物标志物 网络毒理学 靶蛋白 毒性 

分 类 号：R285[医药卫生—中药学]