Study on Hepatotoxicity of Rhubarb Based on Metabolomics and Network Pharmacology.
Study on Hepatotoxicity of Rhubarb Based on Metabolomics and Network Pharmacology.
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基于代谢组学和网络药理学的大黄肝毒性研究
DOI：
10.2147/dddt.s301417
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Li S;Wang Y;Li C;Yang N;Yu H;Zhou W;Chen S;Yang S;Li Y
研究背景大黄作为传统中药，是临床上治疗郁结便秘的首选药物。已有文献报道大黄具有肝毒性，但其在体内的作用机制尚不清楚。方法采用UPLC-Q-TOF/MS结合数据后处理技术对大黄中的化学成分进行鉴定。通过代谢组学技术获得的代谢生物标志物与大黄素诱导的肝毒性有关。通过以上组分及其代谢产物的网络药理学研究，获得了大黄素肝毒性的潜在靶点。同时对共同靶点进行GO基因富集分析和KEGG通路分析。结果基于UPLC-Q-TOF/MS技术鉴定了大黄中28种成分，预测了242个与大黄成分相关的靶标。通过代谢组学技术获得了9个与大黄素肝毒性密切相关的代谢生物标志物，预测了282个代谢物靶点。其中，强啡肽B（10-13）、颈酰乙醇胺、lysoPE（18：2）、3-羟基苯甲酸3-羟基苯酯4种代谢物水平显著升高，多巴胺、生物蝶呤、胆碱、辅酶Q9、P1，P4-双（5-尿苷酰）四磷酸5种代谢物水平显著降低。此外，通过网络药理学方法筛选出166个大黄素肝毒性作用的潜在靶点。对共同靶点进行KEGG通路分析，获得46条相关信号通路。结论大黄可能通过作用于多巴胺D1受体（DRD 1）、多巴胺D2受体（DRD 2）、磷酸二酯酶4 B（PDE 4 B）、香草酸受体（TRPV 1）而引起肝毒性;瞬时受体电位阳离子通道亚家族M成员8（TRPM 8），前列腺素类EP 2受体（PTGER 2），乙酰胆碱酯酶（ACHE），毒蕈碱型乙酰胆碱受体M3（CHRM 3）通过cAMP信号通路、胆碱能突触和炎症介质来调节TRP通道。结合代谢组学技术和网络药理学，探讨大黄的肝毒性，促进大黄的合理临床应用。
Background Rhubarb, as a traditional Chinese medicine, is the preferred drug for the treatment of stagnation and constipation in clinical practice. It has been reported that rhubarb possesses hepatotoxicity, but its mechanism in vivo is still unclear. Methods In this study, the chemical components in rhubarb were identified based on UPLC-Q-TOF/MS combined with data postprocessing technology. The metabolic biomarkers obtained through metabolomics technology were related to rhubarb-induced hepatotoxicity. Furthermore, the potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology involving the above components and metabolites. Meanwhile, GO gene enrichment analysis and KEGG pathway analysis were performed on the common targets. Results Twenty-eight components in rhubarb were identified based on UPLC-Q-TOF/MS, and 242 targets related to rhubarb ingredients were predicted. Nine metabolic biomarkers obtained through metabolomics technology were closely related to rhubarb-induced hepatotoxicity, and 282 targets of metabolites were predicted. Among them, the levels of 4 metabolites, namely dynorphin B (10–13), cervonoyl ethanolamide, lysoPE (18:2), and 3-hydroxyphenyl 2-hydroxybenzoate, significantly increased, while the levels of 5 metabolites, namely dopamine, biopterin, choline, coenzyme Q9 and P1, P4-bis (5ʹ-uridyl) tetraphosphate significantly decreased. In addition, 166 potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology. The KEGG pathway analysis was performed on the common targets to obtain 46 associated signaling pathways. Conclusion These data suggested that rhubarb may cause liver toxicity due to its action on dopamine D1 receptor (DRD1), dopamine D2 receptor (DRD2), phosphodiesterase 4B (PDE4B), vanilloid receptor (TRPV1); transient receptor potential cation channel subfamily M member 8 (TRPM8), prostanoid EP2 receptor (PTGER2), acetylcholinesterase (ACHE), muscarinic acetylcholine receptor M3 (CHRM3) through the cAMP signaling pathway, cholinergic synapses, and inflammatory mediators to regulate TRP channels. Metabolomics technology and network pharmacology were integrated to explore rhubarb hepatotoxicity to promote the reasonable clinical application of rhubarb.
影响因子：
2.4
作者：
Kusumoto C;Kinugawa T;Morikawa H;Teraoka M;Nishida T;Murawaki Y;Yamada K;Matsura T
通讯作者：
Matsura T