Guo Xiao-Hong, Huang Meng-Jun, Wang Li-Juan, Ran Qiang, Yang Sen, Wu Wen-Hui, Zhang Xiao-Qiong, Liu You-Ping
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine Chengdu 611137, China Chongqing 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.
Zhongguo Zhong Yao Za Zhi. 2022 Apr;47(7):1932-1941. doi: 10.19540/j.cnki.cjcmm.20211223.702.
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, target genes, metabolites, and metabolic pathways, this study unveiled the mechanism of potential neurotoxicity, cardiotoxicity, and hepatotoxicity of RMF, which is expected to provide a clue for the basic research on toxic Chinese medicinals.
本研究旨在基于血清代谢组学和网络毒理学探索闹羊花的毒性机制。根据症状、血清生化指标和组织病理学评估闹羊花对正常大鼠的毒性作用。将血清代谢组学与多元统计分析相结合，以寻找内源性差异代谢物和相关代谢途径。通过网络毒理学技术筛选闹羊花的毒性成分、靶点和信号通路，并借助血清代谢组学建立成分 - 靶点 - 代谢物 - 代谢途径网络。结果提示闹羊花具有神经毒性、肝毒性和心脏毒性。血清代谢组学共鉴定出31种差异代谢物和10条主要代谢途径，网络毒理学筛选出11种毒性成分、332个相关靶基因和141条主要信号通路。进一步分析得出7种关键毒性成分：灰安毒素Ⅲ、灰安毒素Ⅰ、光杜鹃素Ⅱ、光杜鹃素Ⅴ、光杜鹃素Ⅵ、光杜鹃素Ⅶ和木藜芦毒素，它们作用于以下12个关键靶点：雄激素受体（AR）、白蛋白（ALB）、雌激素受体β（ESR2）、性激素结合球蛋白（SHBG）、11型羟类固醇（17 - β）脱氢酶（HSD17B11）、雌激素受体α（ESR1）、视黄酸X受体γ（RXRG）、C型乳酸脱氢酶（LDHC）、醛糖酮还原酶（AKR）1C家族成员3（AKR1C3）、ATP结合盒亚家族B成员1（ABCB1）、尿苷二磷酸葡萄糖醛酸基转移酶2B7（UGT2B7）和谷氨酰胺合成酶（GLUL）。这些靶点干扰了γ - 氨基丁酸、雌三醇、睾酮、视黄酸、2 - 氧代丁酸的代谢，并影响了丙氨酸、天冬氨酸和谷氨酸代谢、半胱氨酸和甲硫氨酸代谢、类固醇激素生物合成以及视黄醇代谢这4条关键代谢途径。闹羊花通过多种成分、靶点和途径对多个系统发挥毒性作用。通过对关键毒性成分、靶基因、代谢物和代谢途径的分析，本研究揭示了闹羊花潜在的神经毒性、心脏毒性和肝毒性机制，有望为有毒中药的基础研究提供线索。
