目的 采用代谢组学技术探讨补骨脂提取物（PCE）造成肝损伤的作用机制。方法 将18只大鼠随机分为对照组和PCE低、高剂量(1.8、7.2 g·kg^-1，分别为临床等效剂量和临床4倍等效剂量)组，均连续ig给药28 d。试剂盒法检测血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）、白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α、髓过氧化物酶（MPO）水平；苏木精-伊红（HE）染色后观察肝脏病理学变化。采集各组小鼠的肝脏，HPLCMS分析肝损伤成分—norbakuchinic acid、补骨脂素、异补骨脂素、补骨脂二氢黄酮甲醚、补骨脂查尔酮、补骨脂甲素、补骨脂宁、补骨脂定、新补骨脂异黄酮含量变化；GC-MS代谢组学分析肝脏中内源性代谢物的差异及含量。结果 与对照组相比，PCE低、高剂量组肝生化指标ALT、AST、ALP水平显著升高（P<0.001）；促炎因子IL-6、TNF-α和MPO水平显著上升（P<0.001），肝脏切片表现出肝细胞肿胀，在局部区域观察到少量淋巴细胞呈灶性浸润，甚至出现胞质疏松，肝细胞损伤明显。与PCE低剂量组相比，PCE高剂量组补骨脂素、异补骨脂素、补骨脂定、补骨脂甲素、补骨脂二氢黄酮甲醚、补骨脂查尔酮、补骨脂宁、新补骨脂异黄酮的浓度显著升高，norbakuchinic acid显著降低（P<0.01、0.001）。代谢组学筛选出肌氨酸、丙酮酸、尿素、乳酸、苹果酸、苏氨酸、瓜氨酸、谷氨酸、富马酸、天冬氨酸、甘氨酸等差异代谢物，主要涉及到精氨酸生物合成，甘氨酸、丝氨酸、苏氨酸代谢，丙酮酸代谢等通路。结论 PCE造成肝损伤可能与肝损伤成分剂量相关性蓄积和氨基酸代谢紊乱相关。

Objective To explore the mechanism of Psoralea corylifolia extract（PCE）-induced liver injury by metabolomics. Methods Totally 18 rats were randomly divided into the control group and the low-dose(1.8 g·kg^-1) and high-dose(7.2 g·kg^-1) PCE groups, and were ig administered for 28 days. The levels of serum ALT, AST, ALP, IL-6, TNF-α, and MPO were detected by kits. The pathological changes of the liver were observed after HE staining. The livers of each group were collected, and the contents of liver injury components-norbakuchinic acid, psoralen, isopsoralen, psoralen dihydroflavone methyl ether, psoralen chalcone, psoralen A, psoralen B, psoralen C, and new psoralen isoflavone were analyzed by HPLC-MS. The differences and contents of endogenous metabolites in the liver were analyzed by GC-MS metabolomics. Results Compared with the control group, the levels of ALT, AST, and ALP in the low-dose and high-dose PCE groups were significantly increased（P < 0.001）; the levels of pro-inflammatory factors IL-6, TNF-α, and MPO were significantly increased（P < 0.001）, and the liver sections showed hepatocyte swelling, with a small number of lymphocytes presenting focal infiltration in some areas, and even cytoplasmic loosening, indicating obvious liver cell injury. Compared with the low-dose PCE group, the concentrations of psoralen, isopsoralen, psoralen C, psoralen A, psoralen dihydroflavone methyl ether, psoralen chalcone, psoralen B, and new psoralen isoflavone in the high-dose PCE group were significantly increased, while norbakuchinic acid was significantly decreased（P < 0.01, 0.001）. Metabolomics identified differences in metabolites such as sarcosine, pyruvate, urea, lactic acid, malic acid, threonine, citrulline, glutamic acid, fumaric acid, aspartic acid, and glycine, mainly involving arginine biosynthesis, glycine, serine, and threonine metabolism, and pyruvate metabolism pathways. Conclusion Liver injury caused by PCE may be related to the increase of liver injury components and the disorder of amino acid metabolism.

R965

国家自然科学基金青年项目(82304736); 江苏省中药骨干人才高级研修项目(苏中医科教[2025]11号); 南京中医药大学青年基金项目(XZR2021085)