Lü Jintao, Zhang Dan, Zhang Xiaomeng, Sa Rina, Wang Xiaofang, Wu Huanzhang, Lin Zhijian, Zhang Bing
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
ACS Omega. 2022 Sep 29;7(40):35911-35923. doi: 10.1021/acsomega.2c04579. eCollection 2022 Oct 11.
This study was performed to investigate the herb-drug interactions (HDIs) of citrus herbs (CHs), which was inspired by the "grapefruit (GF) juice effect". Based on network analysis, a total of 249 components in GF and 159 compounds in CHs exhibited great potential as active ingredients. Moreover, 360 GF-related genes, 422 CH-related genes, and 111 genes associated with drug transport and metabolism were collected, while 25 and 26 overlapping genes were identified. In compound-target networks, the degrees of naringenin, isopimpinellin, apigenin, sinensetin, and isoimperatorin were higher, and the results of protein-protein interaction indicated the hub role of UGT1A1 and CYP3A4. Conventional drugs such as erlotinib, nilotinib, tamoxifen, theophylline, venlafaxine, and verapamil were associated with GF and CHs via multiple drug transporters and drug-metabolizing enzymes. Remarkably, GF and CHs shared 48 potential active compounds, among which naringenin, tangeretin, nobiletin, and apigenin possessed more interactions with targets. Drug metabolism by cytochrome P450 stood out in the mutual mechanism of GF and CHs. Molecular docking was utilized to elevate the protein-ligand binding potential of naringenin, tangeretin, nobiletin, and apigenin with UGT1A1 and CYP3A4. Furthermore, in vitro experiments demonstrated their regulating effect. Overall, this approach provided predictions on the HDIs of CHs, and they were tentatively verified through molecular docking and cell tests. Moreover, there is a demand for clinical and experimental evidence to support the prediction.
本研究受“葡萄柚汁效应”启发，旨在探究柑橘类草药（CHs）的药-草相互作用（HDIs）。基于网络分析，葡萄柚中的249种成分和柑橘类草药中的159种化合物显示出作为活性成分的巨大潜力。此外，收集了360个与葡萄柚相关的基因、422个与柑橘类草药相关的基因以及111个与药物转运和代谢相关的基因，同时鉴定出25个和26个重叠基因。在化合物-靶点网络中，柚皮素、异茴芹内酯、芹菜素、甜橙黄酮和异欧前胡素的度数较高，蛋白质-蛋白质相互作用结果表明UGT1A1和CYP3A4起核心作用。厄洛替尼、尼洛替尼、他莫昔芬、茶碱、文拉法辛和维拉帕米等传统药物通过多种药物转运体和药物代谢酶与葡萄柚和柑橘类草药相关联。值得注意的是，葡萄柚和柑橘类草药共有48种潜在活性化合物，其中柚皮素、橘皮素、诺米林和芹菜素与靶点的相互作用更多。细胞色素P450介导的药物代谢在葡萄柚和柑橘类草药的相互作用机制中较为突出。利用分子对接提高了柚皮素、橘皮素、诺米林和芹菜素与UGT1A1和CYP3A4的蛋白质-配体结合潜力。此外，体外实验证明了它们的调节作用。总体而言，该方法对柑橘类草药的药-草相互作用进行了预测，并通过分子对接和细胞试验进行了初步验证。此外，还需要临床和实验证据来支持该预测。
