Zhang Guoqin, Sun Jianhua, Liu Meiqi, Tian Zhixiang, Ma Zicheng, Hao Bingyu, Ning Jintang, Ren Xiaoliang, Wang Meng, Wang Ping, Li Jiunian, Li Hailin, Ni Jian, Liu Yi
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Dongying People's Hospital, Shandong 257091, China.
Biomed Pharmacother. 2023 Apr;160:114233. doi: 10.1016/j.biopha.2023.114233. Epub 2023 Feb 8.
Polygoni multiflori radix (PM) is a well-known tonic herb. It has been reported that PM could cause idiosyncratic inflammatory liver injury in some individuals. In this study, we investigated the mechanism of PM-induced idiosyncratic inflammatory liver injury in zebrafish and rat models based on pharmacodynamics and pharmacokinetics. The zebrafish were administered with polygoni multiflori radix extract (PME), emodin (EMO), and 2,3,5,4'-tetrahydroxystilbene-2-Ο-β-D-glucoside (TSG) after lipopolysaccharide (LPS) treatment, to establish an idiosyncratic inflammation model. In zebrafish with idiosyncratic inflammation, PME, EMO, and TSG decreased liver area and brightness and increased the number of immune cells around the colliculi. PME+LPS produced hepatocyte damage, aggravated mitochondrial and endoplasmic reticulum damage, and increased AST and ALT activity. RT-PCR showed that PME and EMO up-regulated the expression of IL-6, IL-1β, and INF-γ, and PME down-regulated expression of FXR and SHP. In rats with idiosyncratic inflammation, AST and ALT activities increased significantly, and liver tissues showed pathological damage. An efficient and sensitive LC-MS/MS method was established for the pharmacokinetic study of EMO and TSG in rats with idiosyncratic inflammation. The AUC was higher for EMO and TSG in the model group compared with the normal group. The MRT was significantly prolonged in EMO, while CL was significantly reduced. The present results suggested that the absorption of potentially toxic components of PM increased and metabolism slowed down under inflammatory stress, and PM induced idiosyncratic liver injury via the FXR-SHP axis.
何首乌是一种著名的滋补草药。据报道，何首乌在某些个体中可引起特异性炎症性肝损伤。在本研究中，我们基于药效学和药代动力学，研究了何首乌诱导斑马鱼和大鼠模型特异性炎症性肝损伤的机制。在脂多糖（LPS）处理后，给斑马鱼施用何首乌提取物（PME）、大黄素（EMO）和2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷（TSG），以建立特异性炎症模型。在患有特异性炎症的斑马鱼中，PME、EMO和TSG减小了肝脏面积和亮度，并增加了视丘周围免疫细胞的数量。PME+LPS导致肝细胞损伤，加重线粒体和内质网损伤，并增加AST和ALT活性。RT-PCR显示，PME和EMO上调IL-6、IL-1β和INF-γ的表达，而PME下调FXR和SHP的表达。在患有特异性炎症的大鼠中，AST和ALT活性显著增加，肝脏组织出现病理损伤。建立了一种高效灵敏的LC-MS/MS方法，用于对患有特异性炎症的大鼠体内EMO和TSG进行药代动力学研究。与正常组相比，模型组中EMO和TSG的AUC更高。EMO的MRT显著延长，而CL显著降低。目前的结果表明，在炎症应激下，何首乌潜在毒性成分的吸收增加，代谢减慢，并通过FXR-SHP轴诱导特异性肝损伤。
