National Institutes for Food and Drug Control, Beijing 102629, China.
State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Toxins (Basel). 2022 Nov 5;14(11):765. doi: 10.3390/toxins14110765.
The traditional Chinese herbal medicine Turcz. () has been widely adopted to treat nausea, diabetes, siriasis, and poor appetite. However, contains multiple pyrrolizidine alkaloids (PAs). This study aimed to investigate the hepatotoxicity of total alkaloids in (EFTAs) and identify the toxic mechanisms of EFTAs on hepatocytes. Liquid chromatography with a tandem mass spectrometry assay with reference standards indicated that EFTAs mainly consisted of eight PAs whose content accounted for 92.38% of EFTAs. EFTAs markedly decreased mouse body and liver weights and increased the contents of AST and ALT. The histopathological assays demonstrated that, after exposition to EFTAs, the structures of hepatocytes were damaged and the fibrosis and apoptosis in hepatocytes were accelerated. Moreover, EFTAs increased the serum level of inflammatory cytokines and aggravated circulating oxidative stress. A combination of hepatic proteomics and metabolomics was used to investigate the toxic mechanisms of EFTAs. The study revealed that EFTAs seriously disrupted glycerophospholipid metabolism by upregulating the contents of lysophosphatidylglycerol acyltransferase 1 and phosphatidylinositol and downregulating the contents of choline/ethanolamine kinase beta, choline-ethanolamine phosphotransferase 1, phospholipase D4, 1-acylglycerophosphocholine, phosphatidylcholine, and dihydroxyacetone phosphate in the liver, resulting in detrimental inflammation, fibrosis, and apoptosis. This study revealed that EFTAs induced severe hepatotoxicity by disrupting glycerophospholipid metabolism.
中药土木香（）已被广泛用于治疗恶心、糖尿病、乙型脑炎和食欲不振。然而，土木香含有多种吡咯里西啶生物碱（PAs）。本研究旨在探讨土木香总生物碱（EFTAs）的肝毒性，并确定 EFTAs 对肝细胞的毒性机制。采用液相色谱-串联质谱联用（LC-MS/MS）检测法和参考标准品，结果表明 EFTAs 主要由 8 种 PAs 组成，其含量占 EFTAs 的 92.38%。EFTAs 明显降低了小鼠的体重和肝脏重量，并增加了 AST 和 ALT 的含量。组织病理学检测表明，EFTAs 暴露后，肝细胞结构受损，肝纤维化和细胞凋亡加速。此外，EFTAs 增加了血清中炎症细胞因子的水平，并加重了循环氧化应激。本研究采用肝蛋白质组学和代谢组学相结合的方法，探讨了 EFTAs 的毒性机制。研究结果表明，EFTAs 通过上调溶血磷脂酰甘油酰基转移酶 1 和磷脂酰肌醇的含量，下调胆碱/乙醇胺激酶β、胆碱-乙醇胺磷酸转移酶 1、磷脂酶 D4、1-酰基甘油磷酸胆碱、磷脂酰胆碱和二羟丙酮磷酸的含量，严重扰乱了甘油磷脂代谢，导致炎症、纤维化和细胞凋亡。本研究表明，EFTAs 通过扰乱甘油磷脂代谢，导致严重的肝毒性。
