| 摘要: |
| 【目的】探讨阿司匹林（ASA）、保泰松（PTZ）、吲哚美辛（IDM）、吡罗昔康（PRX）、氟比洛芬（FBP）等5种非甾体类抗炎药（NSAIDs）对小鼠肝脏的损伤作用，为研究NSAIDs对肝损伤的作用机制提供参考。【方法】将70只昆明小白鼠，随机分为正常对照组（NC）、对乙酰氨基酚阳性对照组（APAP）、ASA组、PTZ组、IDM组、PRX组和FBP组，每组10只，NC组灌胃质量分数0.5% CMC-Na，APAP组灌胃70 mg/kg APAP，ASA组、PTZ组、IDM组、PRX组和FBP组分别灌胃50，54，2.4，2.6和7.5 mg/kg剂量的相应NSAIDs，每天2次，连续3 d；末次给药12 h后，眼丛静脉采血分离血清并采集肝脏样品，检测血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平及肝脏氧化指标（丙二醛（MDA）、谷胱甘肽（GSH）含量及超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）的活性）；苏木精-伊红染色进行肝组织病理组织形态学观察，评价肝脏损伤程度；体外提取正常小鼠肝线粒体，将5种NSAIDS梯度稀释，使ASA、PTZ和PRX配置浓度均为64，128，256和512 μmol/L，IDM和FBP配制浓度为32，64，128和256 μmol/L，然后与线粒体共孵育并检测CYP2E1的活性，检测5种NSAIDs对肝脏CYP2E1活性的影响，进一步探究NSAIDs诱导肝损伤的潜在作用机制。【结果】除PRX外，其余4种NSAIDs均可不同程度使小鼠AST、ALT和MDA水平升高，降低抗氧化防御系统SOD、GSH和GSH-Px的水平；肝脏病理学观察发现，PRX对肝组织几乎无损伤作用，ASA的急性肝损伤作用较弱，IDM、FBP和PTZ对小鼠肝脏损伤作用较强，主要表现为边缘圆钝，肝体发黄；镜下观察为肝细胞颗粒变性，并伴有肝细胞坏死，小叶间结构不清晰，沿中央静脉和肝索分布有一定数量的炎性细胞。体内外试验均表明，IDM、FBP和PTZ能够诱导CYP2E1，而PRX和ASA对CYP2E1几乎无显著诱导作用。【结论】5种NSAIDs类药物中，PRX对肝组织无损伤作用，ASA对小鼠肝脏损伤作用较小，IDM、FBP和PTZ可能通过诱导CYP2E1导致线粒体功能障碍而引发肝脏损伤。 |
| 关键词: 非甾体类抗炎药 氧化应激 CYP2E1 肝损伤 小鼠 |
| DOI： |
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| 基金项目:甘肃农业大学盛彤笙基金项目（GSAU-STS-1729）；甘肃农业大学动物医学院教研产学支持项目（JYCX-KX017）；甘肃省教育厅高校科研项目（2018A-034） |
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| Damages of five non-steroid anti-inflammatory drugs to mice liver |
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WANG Meng,PAN Yangyang,YUE Yahui,et al
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| Abstract: |
| 【Objective】This study explored the damaging effects of 5 different non-steroid anti-inflammatory drugs (NSAIDs) on mice liver to provide reference for NSAIDs application and mechanism study.【Method】Seventy Kunming mice were randomly divided into 7 groups of normal control group (NC),acetaminophen positive control group (APAP),acetylsalicylic acid group (ASA),and phenylbutazone group (PTZ),indomethacin group (IDM),piroxicam group (PRX) and flurbiprofen group (FBP).ASA (50 mg/kg),PTZ (54 mg/kg),IDM (2.4 mg/kg),PRX (2.6 mg/kg),FBP (7.5 mg/kg) were intragastrically administered twice a day for 3 consecutive days to mice in related groups,respectively.Twelve hours after last administration,serum was separated,and liver tissue was collected.Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels,as well as liver malondialdehyde (MDA),glutathione (GSH),superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were detected.Pathological histomorphology of liver tissue was used to evaluate liver damage.Then,the effects of 5 NSAIDs on liver CYP2E1 activity were tested both in vivo and in vitro.【Result】 Except for PRX,other 4 NSAIDs significantly increased AST,ALT and MDA levels,while decreased antioxidative defense levels of SOD,GSH and GSH-Px in mice.According to liver pathology observations,less acute liver injury occurred in ASA treated mice and no liver injury existed in PRX mice.IDM,FBP and PTZ caused strong liver damages.Pathological sections showed rounded edges and yellow liver,while microscope showed hepatocyte granular degeneration accompanied by hepatocyte necrosis.The structure of lobules was not clear along center and there were inflammatory cells distributed in vein and liver cord.IDM,FBP and PTZ increased CYP2E1 activities both in vivo and in vitro,while PRX and ASA had no significant effect on CYP2E1.【Conclusion】Among tested NSAIDs,PRX caused no damage,ASA slightly induced liver injury,while IDM,FBP and PTZ led to liver injury by inducing mitochondrial dysfunction through CYP2E1 induction. |
| Key words: non-steroid anti-inflammatory drugs oxidative stress CYP2E1 liver injury mice |
