对乙酰氨基酚对不同妊娠期小鼠肝肾功能的影响及机制研究

Effects of APAP on liver and kidney function in different pregnancy stage and related mechanism

目的研究对乙酰氨基酚(acetaminophen,APAP)对不同妊娠期小鼠肝肾功能的影响及其机制。方法分别给予未妊娠、妊娠中期和晚期小鼠500 mg·kg^(-1)APAP(文献报道最大可耐受剂量)后,于0、6、24、48 h取材,全自动生化仪测定肝脏和肾脏的血液生化指标;LC-MS/MS的cocktail探针法测定CYP450s代谢酶活性;HE染色法观察肝、肾组织病理学变化;LC-MS/MS法测定APAP活性代谢产物N-乙酰-对苯醌亚胺(NAPQI)-GSH结合物。结果小鼠肝CYP450s活性在妊娠中期上调,而在妊娠晚期恢复到正常水平;小鼠肝SOD活性在妊娠中期和晚期均上调,而肝脏GSH水平仅在妊娠中期明显高于未妊娠组。APAP可致妊娠中期小鼠产生轻微肝损伤,主要表现为ALT、AST、ALP、MDA水平升高(P<0.05),而SOD和GSH含量降低,同时其肝脏中的NAPQI-GSH水平明显升高(P<0.05)。APAP对未妊娠和妊娠晚期小鼠肝功能影响较小,APAP对妊娠各期小鼠肾功能无明显影响。结论 500 mg·kg^(-1)APAP仅致妊娠中期小鼠产生急性轻微肝损伤,这可能与妊娠中期小鼠肝CYP450s活性升高,但同时伴随肝SOD活性和GSH水平升高有关。

Aim To observe the effects of acetaminophen（APAP） on liver and kidney function in mice with different gestational ages. Methods 500 mg ·kg-1 APAP was given to non-preganancy, middle preganancy and late-pregnancy mice by oral administration,then they were sacrificed at 0,6,24 and 48 h. The changes of alanine aminotransferase（ALT）,aspartate transaminase（AST）,alkaline phosphatase（ALP）,blood urea nitrogen（BUN）,creatinine and antioxidation indices superoxide dismutase（SOD）,malonic dialdehyde（MDA）,glutathione（GSH） and liver,kidney histological evaluation were determined.The activity of liver CYP450 s and contents of liver NAPQI were detected by LC-MS/MS method. Results500 mg · kg-1 APAP only caused mild liver injury in mice with mid-pregnancy as reflected by the increased of ALT,AST and ALP levels. Besides,the CYP450 s activity,SOD activity and GSH contents were significantly up-regulated in mid-pregnancy mice.What＇s more,500 mg·kg-1 APAP has less effect on non-preganancy and late-preganancy mice liver function. Also,no effect was observed on the mice kidney function in all groups. Conclusion In conclusion,500 mg·kg-1 APAP can induce mild acute liver injury in mice during the mid-pregnancy,which may be explained by the increase of CYP450 s activity,SOD activity and GSH contents.