基于代谢组学方面对氯胺酮肝毒性的机制研究

Study on mechanism of ketamine hepatotoxicity based on metabonomic

目的从代谢组学层面对氯胺酮肝毒性及其机制进行研究。方法选择48只SD大鼠为实验动物,将其分为氯胺酮组(50 mg·kg-1·d-1)和对照组(等量生理盐水),每组24只,均腹腔注射给药。分别在给药1、4、12周后每组取8只大鼠,测定其肝脏指数,检测血清ALT、AST水平,IL-6和TNF-α炎症指标,观察肝组织病理学变化;同时运用气相色谱-质谱法(GC-MS)分析血清代谢物变化。结果与对照组比较,氯胺酮组在给药12周后体质量明显减轻(P<0.05);肝脏指数在给药4、12周后明显增加(P<0.05);血清ALT、AST,IL-6、TNF-α水平在给药12周后均明显升高(P<0.01);肝组织细胞受损,出现明显病理性改变。氯胺酮组和对照组血清代谢物水平发生明显改变,差异代谢通路涉及D-谷氨酰胺和D-谷氨酸代谢;丙氨酸、天冬氨酸和谷氨酸代谢;苯丙氨酸、酪氨酸和色氨酸代谢;苯丙氨酸代谢;缬氨酸、亮氨酸和异亮氨酸代谢。结论氯胺酮肝毒性机制主要涉及氨基酸多条代谢通路,体现在能量代谢、氧化应激、神经递质传递等的异常反应。

Objective To study the hepatotoxicity and mechanism of ketamine from the metabonomic level.Methods Forty-eight SD rats served as the experimental animals and divided into the ketamine group(50 mg·kg-1·d-1)and control group(same volume of normal saline),24 cases in each group.The medication was given by intraperitoneal injection.After 1,4,12 weeks of drug administration,8 cases in each group were taken for measuring the liver index,serum ALT and AST levels,IL-6 and TNF-α inflammatory indicators,and the liver histopathological changes were observed.Meanwhile,the changes of serum metabolites were analyzed by using the gas chromatography-mass spectrometry(GC-MS).Results Compared with the control group,the body mass after 12 weeks of administration in the ketamine group was significantly decreased(P<0.05).The liver index at 4,12 weeks of medication was increased significantly(P<0.05).The levels of serum ALT,AST,IL-6 and TNF-αat 12 weeks after medication was increased significantly(P<0.01).The liver tissue cells were damaged and showed obvious pathological changes.Serum metabolite levels in the ketamine group and control group were significantly changed,and the different metabolic pathways involved D-glutamine and D-glutamic acid metabolism;alanine,aspartic acid and glutamic acid metabolism;phenylalanine,tyrosine and tryptophan metabolism;phenylalanine metabolism;valine,leucine and isoleucine metabolism.Conclusion The ketamine hepatotoxicity mechanism mainly involves in multiple amino acid metabolic pathways,which are reflected in abnormal reactions of energy metabolism,oxidative stress and neurotransmitter transmission.