目的 通過整合血清代謝組學(xué)和網(wǎng)絡(luò)毒理學(xué)，探究大青葉腎毒性成分及機制。方法 采用大鼠連續(xù)90 d給藥評價大青葉腎毒性作用。通過血清代謝組學(xué)尋找差異代謝物及代謝通路；采用網(wǎng)絡(luò)毒理學(xué)分析大青葉潛在腎毒性成分和靶點；整合血清代謝組學(xué)和網(wǎng)絡(luò)毒理學(xué)，構(gòu)建“成分-靶點-代謝物-代謝通路”網(wǎng)絡(luò)。結(jié)果 大青葉具有一定腎毒性。血清代謝組學(xué)結(jié)果顯示67個代謝物水平發(fā)生顯著變化，涉及5條主要代謝通路；網(wǎng)絡(luò)毒理學(xué)篩選出32個毒性成分，對應(yīng)靶點422個，相關(guān)通路189條。整合分析篩選出左旋樟腦、胭木二酮、正辛醛、(-)-α-蒎烯、靛藍、十四烷等6個毒性成分，作用于PTGS2、PTGS1、SRC、CYP2A6、CYP1A2、CYP1A1等27個靶點，干擾檸檬酸、花生四烯酸、白三烯C4、吡哆醇4種代謝物，影響丙氨酸、天冬氨酸和谷氨酸代謝，花生四烯酸代謝，氨基酸生物合成，維生素B6代謝4條代謝通路。結(jié)論 結(jié)合血清代謝組學(xué)和網(wǎng)絡(luò)毒理學(xué)初步闡明了大青葉腎毒性成分及機制，為大青葉臨床安全合理應(yīng)用提供了參考。

Objective To explore nephrotoxic components and mechanisms of Isatidis Folium (IF) by integrating serum metabolomics and network toxicology. Methods The nephrotoxic effect of IF was evaluated by continuous administration in rats for 90 d. Search for differential metabolites and metabolic pathways through serum metabolomics. The potential nephrotoxic components and targets of IF were analyzed by network toxicology. Integrate serum metabolomics and network toxicology to construct a "component-target-metabolitemetabolic pathway" network. Results IF has certain nephrotoxicity. The results of serum metabolomics showed significant changes in the levels of 67 metabolites, involving five major metabolic pathways. Network toxicology screened out 32 toxic components, corresponding to 422 targets and 189 related pathways. Integrated analysis screened out six toxic components, including L-camphor, wrightiadione, octanal, (-)-α-pinene, indigo and tetradecane, which could act on 27 targets, including PTGS2, PTGS1, SRC, CYP2A6, CYP1A2, CYP1A1, etc. These targets interfered with the metabolism of citric acid, arachidonic acid, leukotriene C₄, pyridoxine, and affected four key metabolic pathways of alanine, aspartate and glutamate metabolism, arachidonic acid metabolism, biosynthesis of amino acids, and vitamin B6 metabolism. Conclusion Combined with serum metabolomics and network toxicology, the components and mechanisms of nephrotoxicity of IF were elucidated, which provided reference for safe and rational clinical application of IF.

R965.3

國家自然科學(xué)基金項目（82260681）；蒙藥研發(fā)國家地方聯(lián)合工程研究中心開放基金資助項目（MDK2025004）