Exploring the liver toxicity mechanism of Tripterygium wilfordii extract based on metabolomics, network pharmacological analysis and experimental validation

作者：Guoliang Zhou, Shulan Su, Li Yu, Erxin Shang, Yongqing Hua, Hao Yu, Jin-Ao Duan · 发表于：Journal of Ethnopharmacology · 年份：2024 · DOI：10.1016/j.jep.2024.118888 · 被引用次数：24 · 研究领域：Natural Compounds in Disease Treatment、Flavonoids in Medical Research、Rheumatoid Arthritis Research and Therapies

Tripterygii wilfordii Radix, (TW) as a toxic herbal medicine, is the root of Tripterygium wilfordii Hook. F. , which commonly used in China for the treatment of rheumatoid arthritis and autoimmune diseases, but its severe toxicity, particularly hepatotoxicity, significantly impacts its clinical application. The hepatotoxicity and its molecular mechanism of 70% TW ethanol extract (TWE) on male mice were demonstrated based on metabolomics, network pharmacological analysis and experimental validation. The toxic and bioactive ingredients in TWE were quantitative analyzed by Triple quadrupole (TQ) mass spectrometry method. The liver organ index, as well as the liver function indexes AST and ALT were evaluated after administering different doses of TWE for 24 h, and a pathological change was analyzed in liver tissue. Non-targeted metabolomics using UPLC-QTOF/MS was performed on both the plasma and liver tissue samples in combination with network toxicology to screen for key targets related to TWE toxicity in the liver. These key targets including caspase 3, NF- κ B, TLR4, TNF- α , NQO1, and Bcl2 were subsequently verified through Western blotting experiments. The six toxic and active ingredients of raphenolactone, ranolactone, triptolide tripterine, wilforlide A, demethylzeylasterain in TWE for the contents of 0.709, 1.408, 0.353, 0.354, 0.882, 0.227 mg g −1 , respectively. Alanine aminotransferase (ALT ) and aspartate aminotransferase (AST) levels increased and liver index decreas...