ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Ethnopharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1585186
A novel strategy for identifying hepatotoxic constituents in traditional Chinese medicine using dose-normalized intracellular accumulation as a cytotoxicity indicator: A case study of Jinlingzi San
Provisionally accepted
- 1Shenyang Pharmaceutical University, shenyang, China
- 2Nankai University, Tianjin, China
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Herb-induced liver injury associated with traditional Chinese medicine (TCM) has increasingly attracted scientific attention. However, the rapid and effective methods for elucidating the material basis of hepatotoxicity in TCM are still lacking. This study developed a strategy based on the use of dose-normalized intracellular accumulation as a cytotoxicity indicator to identify key hepatotoxic components in TCM. Jinlingzi San (JLZS) composed of Fructus Toosendan (FT) and Rhizoma Corydalis (RC) was used as a model sample. The hepatic toxicity of JLZS extract through 14-d continuous gavage administration to rats and after a 24 h co-incubation with L-02 cells were investigated. The chemical components in JLZS extract and accumulated in L-02 cells were identified by LC-MS/MS. The intracellular accumulations of multiple components after exposing L-02 cells to the extracts of JLZS, FT and RC were determined. As a result, JLZS could cause the subacute liver injury and cytotoxicity to L-02 cells. Seven analytes (coptisine, tetrahydrocoptisine, berberine, jatrorrhizine, palmatine, dehydrocorydaline and toosendanin) were identified from the cell lysates after L-02 incubating with JLZS containing medium. Coptisine and berberine were regarded as the main potential hepatotoxic components in JLZS for its highest dose-normalized intracellular accumulation and the strongest cytotoxicity.In addition, we found that the intracellular accumulations of coptisine and berberine in JLZS group were lower than those of in RC group, which maybe reflect the scientific meaning of detoxicity by compatibility with FT and RC. Dose-normalized intracellular accumulation proved to be a potential indicator of cytotoxicity for identifying hepatotoxic constituents in TCM.
Keywords: Traditional Chinese medicines, hepatotoxicity, dose-normalized intracellular accumulation, LC-MS/MS, Jinlingzi San HILI, herb-induced liver injury, TCM, traditional Chinese medicine, JLZS, Jinlingzi San, FT, Fructus Toosendan, RC, Rhizoma Corydalis, TSN, toosendanin, COR, corydaline, THP, tetrahydropalmatine
Received: 28 Feb 2025; Accepted: 23 Apr 2025.
Copyright: © 2025 Wang, Li, Wu, Gu and Di. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaoting Gu, Nankai University, Tianjin, China
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