UGTs-mediated metabolic interactions contribute to enhanced anti-inflammation activity of Jinhongtang
UGTs-mediated metabolic interactions contribute to enhanced anti-inflammation activity of Jinhongtang
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UGT介导的代谢相互作用有助于增强金红汤的抗炎活性
DOI：
10.1016/j.jep.2022.116016
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发表时间：
2023
影响因子：
5.4
通讯作者：
Xiaochi Ma
中科院分区：
文献类型：
--
作者：
Fan Wu;Yan Wang;Quanxi Mei;Qinhua Chen;Chengpeng Sun;Xia Lv;Lei Feng;Chao Wang;Yanyan Zhang;Bangjiang Fang;Xiaokui Huo;Xiangge Tian;Xiaochi Ma
民族药理相关性金红汤是一种中药配方，由掌叶大黄的干茎组成。和大血藤[Sargentodxa cuneata(Oliv.)Rehder&E.H.Wilson(木通科)和蒲公英全株。目的从药代动力学相互作用的角度探讨金红汤的配伍机制。材料与方法采用CLP诱导的小鼠脓毒症模型和脂多糖诱导的RAW264.7细胞模型，观察金红汤与中药的抗炎作用。研究了金红汤有效成分(大黄酸、大黄素、芦荟大黄素)在大鼠体内的药代动力学。结果金红汤对CLP诱导的脓毒症小鼠和脂多糖诱导的RAW264.7小鼠RAW264.7细胞的抗炎作用明显强于单味药。其次，活性成分(大黄酸、大黄素和芦荟大黄素)的生物利用度。当与S联合给药时，通过减少代谢清除，手掌症状显著改善。楔形和T。对金红汤进行体内药代动力学研究，提出了合理的中药配伍机理。具体地说，组件INS。楔形和T。大血藤皂苷A、香草素Ia、栎素和木犀草素可抑制UGT1A9介导的有效成分INR的葡萄糖醛酸化反应。μM、μM、μM和μM的Ki值分别为2.72、1.2 5、2.84和0.83。蒙古和S。金红汤的佐剂楔叶能降低体内关键活性成分OFR的代谢清除量。通过抑制UGT，延长其作用时间，进一步增强其抗炎活性。我们的研究结果为中药合理配伍提供了深刻的见解，并为中药方剂的开发提供了有益的指导。
Ethnopharmacological relevanceJinhongtang, a traditional Chinese medicine (TCM) formula consisting of dry stems ofRheum palmatumL. (Polygonaceae) andSargentodoxa cuneata(Oliv.) Rehder & E.H.Wilson (Lardizabalaceae) and whole plant ofTaraxacum mongolicumHand.-Mazz. (Asteraceae), is widely used for the treatment of infection diseases including severe sepsis and COVID-19.Aim of the studyThe present study aimed to explore the compatibility mechanism in the prescription of Jinhongtang based on the pharmacokinetic interaction.Materials and methodsCLP-induced sepsis mice and LPS-induced RAW264.7 cells were used to explore the anti-inflammatory effect of Jinhongtang and herbs in this clinical prescription. Pharmacokinetics of active components in Jinhongtang (Rhein, Emodin and Aloe emodin) was studied in rats. In vitro analysis of metabolic pathways and interactions mediated by metabolic enzymes were conducted using human liver microsomes (HLMs) and recombinant UGT isoforms.ResultsJinhongtang exhibited much more potent anti-inflammatory effect than its single herbs on CLP-induced sepsis mice and LPS-induced RAW264.7 cells. Next, the bioavailability of active ingredients (Rhein, Emodin and Aloe emodin) inR. palmatumwas significantly improved through reduced metabolic clearance when co-administered withS. cuneataandT. mongolicumas Jinhongtang during thein vivopharmacokinetic study, which presented the rational herbal compatibility mechanism. In detailed, the components inS. cuneataandT. mongolicumincluding Sargentodoxoside A, Chanitracin Ia, Quercetin and Luteolin inhibited the UGT1A9-mediated glucuronidation of active ingredients inR. palmatum,with Kivalues of 2.72 μM, 1.25 μM, 2.84 μM and 0.83 μM, respectively.ConclusionT. mongolicumandS. cuneata, the adjuvant herbs of Jinhongtang, could reduce the metabolic clearance of key active components ofR. palmatum, prolong their action time and further enhance their anti-inflammatory activity via inhibition of UGTs. Our findings provided deep insight for the rational compatibility of TCMs and useful guidance for the development of TCM formula.