Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201204, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Phytomedicine. 2021 Apr;84:153513. doi: 10.1016/j.phymed.2021.153513. Epub 2021 Feb 18.
Huangqi decoction (HQD) has been used to treat chronic liver diseases since the 11th century, but the effective components in HQD against liver fibrosis have not been definitively clarified.
To investigate and identify multiple effective components in HQD against liver fibrosis using a pharmacokinetics-based comprehensive strategy.
The absorbed representative components in HQD and their metabolites were detected in human plasma and urine using high-resolution mass spectrometry combined with a database-directed method, and then pharmacokinetics in multiple HQD components in human plasma was analyzed by ultra-performance liquid chromatography coupled with triple-quadruple mass spectrometry. Furthermore, the anti-fibrotic effect of potential effective HQD components was studied in LX-2 cells and that of a multi-component combination of HQD (MCHD) was verified in a mouse CCl-induced hepatic fibrosis model.
Twenty-four prototype components in HQD and 17 metabolites were identified in humans, and the pharmacokinetic characteristics of 14 components were elucidated. Among these components, astragaloside IV, cycloastragenol, glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin, and isoliquiritigenin downregulated the mRNA expression of α-SMA; cycloastragenol, calycosin-7-O-β-D-glucoside, formononetin, glycyrrhetinic acid, liquiritin, and isoliquiritin downregulated the mRNA expression of Col I; and calycosin, liquiritigenin, isoliquiritigenin, cycloastragenol, and glycyrrhetinic accelerated the apoptosis of LX-2 cells. MCHD reduced serum aminotransferase activity and hepatic collagen fibril deposition in mice with CCl-induced hepatic fibrosis.
Using the pharmacokinetics-based comprehensive strategy, we revealed that multiple effective HQD components act together against liver fibrosis.
黄芪汤自 11 世纪以来一直用于治疗慢性肝病，但黄芪汤抗肝纤维化的有效成分尚未明确。
采用基于药代动力学的综合策略，研究并鉴定黄芪汤抗肝纤维化的多种有效成分。
采用高分辨质谱结合数据库导向法检测人血浆和尿液中黄芪汤的吸收代表性成分及其代谢物，并用超高效液相色谱-三重四极杆质谱法分析人血浆中多种黄芪汤成分的药代动力学。此外，还研究了潜在有效黄芪汤成分在 LX-2 细胞中的抗纤维化作用，并在 CCl 诱导的小鼠肝纤维化模型中验证了黄芪汤多成分组合（MCHD）的抗纤维化作用。
在人体内鉴定出 24 种黄芪汤原型成分和 17 种代谢产物，阐明了 14 种成分的药代动力学特征。其中，黄芪甲苷 IV、环黄芪醇、甘草酸、甘草次酸、甘草素和异甘草素下调α-SMA 的 mRNA 表达；环黄芪醇、毛蕊异黄酮-7-O-β-D-葡萄糖苷、芒柄花素、甘草次酸、甘草苷和异甘草苷下调 Col I 的 mRNA 表达；毛蕊异黄酮、甘草素、异甘草素、环黄芪醇和甘草次酸加速 LX-2 细胞凋亡。MCHD 降低了 CCl 诱导的肝纤维化小鼠血清转氨酶活性和肝胶原纤维沉积。
采用基于药代动力学的综合策略，我们揭示了多种有效的黄芪汤成分协同作用抗肝纤维化。
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