目的 探究黄芩配伍栀子后对正常大鼠肝毒性的影响及其潜在作用机制。方法 采用高效液相色谱法检测栀子单煎、栀子黄芩合煎对栀子苷溶出率的影响。SD大鼠随机分为对照组、栀子（5.6 g/kg）组和栀子黄芩组，ig栀子单煎液、栀子黄芩（1∶1）合煎液5 d后，检测大鼠肝功能指标并观察大鼠肝组织病理变化；采用液质联用技术结合代谢组学方法，对各组间筛选出的差异代谢物进行富集通路，并对各组大鼠血清胆汁酸进行定量分析。结果 相较于栀子单煎，栀子黄芩合煎后栀子苷溶出率降低。与对照组比较，栀子组大鼠肝组织损伤严重，血清肝功能指标水平显著升高（P＜0.01）。配伍黄芩后，大鼠肝组织病理损伤明显减轻，肝功能指标水平显著降低（P＜0.01），表明黄芩配伍栀子能够有效改善肝脏病理损伤。共筛选出包括一磷酸腺苷、α-酮戊二酸、牛磺鹅去氧胆酸、甘氨鹅去氧胆酸等490个潜在的差异代谢物，主要涉及FoxO信号通路、胆固醇代谢等9条关键代谢通路。血清胆汁酸定量分析结果表明，栀子组各初级胆汁酸、次级胆汁酸含量发生不同程度的变化，结合型胆汁酸比例降低，游离型胆汁酸比例升高。而配伍黄芩后，胆汁酸比例失调得到明显改善，胆汁酸稳态恢复。结论 黄芩配伍栀子能够通过降低毒性物质栀子苷的溶出，影响FoxO信号通路、胆固醇代谢等胆汁酸代谢相关通路，改善栀子导致的胆汁酸淤积，恢复胆汁酸稳态，发挥降低肝毒性的作用。

Objective To explore the effect and potential mechanisms of Huangqin (Scutellariae Radix, SR) combined with Zhizi (Gardeniae Fructus, GF) on liver toxicity in normal rats. Methods High performance liquid chromatography was used to detect the effect of GF single decoction and combined decoction of GF and SR on the dissolution rate of geniposide. SD rats were randomly divided into control group, GF (5.6 g/kg) group and GF-SR group. After 5 d of treatment with GF single decoction or GF-SR (1∶1) decoction, liver function indicators were measured and pathological changes in liver tissue of rats were observed. Liquid chromatography-mass spectrometry technology combined with metabolomics methods were performed, the differential metabolites screened between groups were enriched in pathways, and the serum bile acids of rats in each group were quantitatively analyzed. Results Compared with GF single decoction, the dissolution rate of geniposide was decreased after the combined decoction of GF and SR. Compared with control group, rats in GF group had severe liver tissue damage and significantly increased serum liver function indicators (P < 0.01). After compatibility with SR, the pathological damage to liver tissue was significantly reduced, and the levels of liver function indicators were significantly decreased (P < 0.01), indicating that the combination of SR and GF could effectively improve liver pathological damage. A total of 490 potential differential metabolites were screened among the three groups, including adenosine monophosphate, α-ketoglutaric acid, taurochenodeoxycholic acid, glycine chenodeoxycholate, etc., mainly involving nine key metabolic pathways related to FoxO signaling pathway and cholesterol metabolism. The quantitative analysis of serum bile acids showed that the contents of primary and secondary bile acids in GF group changed to varying degrees, with a decrease in the proportion of bound bile acids and an increase in the proportion of free bile acids. After compatibility with SR, the imbalance of bile acid ratio was significantly improved, and the bile acid homeostasis was restored. Conclusion The combination of SR and GF can reduce the dissolution of toxic substances geniposide, and affecting bile acid metabolic-related pathways such as the FoxO signaling pathway and cholesterol metabolism, improve bile acid accumulation caused by GF, restore bile acid homeostasis, and play a role in reducing liver toxicity.

R285.5

山西省基础研究计划基金资助项目（202403021221197）；山西中医药大学科技创新团队基金资助项目（2022TD1016）；山西中医药大学学科建设项目（中药药理与毒理学）