化合物ALI-57对小鼠急性药物性肝损伤活性的初步评价

Preliminary Evaluation of the Activities Against Acute Drug-induced Liver Injury in Mice by Compound ALI-57

关键词:  药物性肝损伤  对乙酰氨基酚  氧化应激  活性评价

Key words:  drug-induced liver injury  acetaminophen  oxidative stress  activity evaluation

摘要:

目的 初步评价化合物ALI-57对对乙酰氨基酚诱导的急性药物性肝损伤活性。方法 48只C57/BL6小鼠随机分为6组，即正常组、模型组、阳性对照组(乙酰半胱氨酸300 mg·kg^–1)和化合物ALI-57低、中、高剂量组(75，150，300 mg·kg^–1)，每组8只。连续灌胃给药3 d，末次给药1 h后，除正常组外其余各组小鼠按350 mg·kg^–1的剂量腹腔注射对乙酰氨基酚进行造模，禁食不禁水，8 h后腹腔静脉取血，进行血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)，肝组织中丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽(GSH)以及谷氨酸脱氢酶(GDH)的检测；提取肝组织用于病理HE染色检查。结果 与正常组比较，模型组血清中ALT、AST水平显著升高，肝组织中MDA和GDH含量升高，而SOD和GSH活性水平下降，组织HE病理染色结果显示肝组织损伤明显增加。与模型组比较，化合物ALI-57中、高剂量组血清中ALT、AST水平显著降低(P<0.05)，肝组织中MDA和GDH含量明显下降(P<0.05)，而肝组织中SOD和GSH活性水平显著升高(P<0.05)，低剂量组与模型组比较无显著性差异。结论 化合物ALI-57能够通过降低氧化应激和提高抗氧化能力对对乙酰氨基酚诱导的急性药物性肝损伤发挥明显的保护作用。

Abstract:

OBJECTIVE To preliminarily evaluate the activities of the compound ALI-57 against acute drug-induced liver injury induced by acetaminophen. METHODS Forty eight C57/BL6 mice were randomly divided into 6 groups with 8 mice in each group as normal group, model group, positive control group(acetylcysteine 300 mg·kg^-1), and compound ALE-57 low, medium, high dose group(75, 150, 300 mg·kg^-1). They were treated with corresponding drugs for 3 d. One hours after the final treatment, acetylcysteine(350 mg·kg^-1) was administrated intraperitoneally to each group except normal group. Fasting without water and blood was collected from celiac vein 8 h later. Alanine aminotransferase(ALT), aspartate aminotransferase(AST) in serum, malondialdehyde(MDA), superoxide dismutase(SOD), glutathione(GSH) and glutamate dehydrogenase(GDH) in liver tissue were determined, HE staining was used to observe the histopathological changes of liver. RESULTS Compared with normal group, the levels of ALT and AST in serum of model group were significantly increased, while the contents of MDA and GDH in liver tissue were increased and the activities of SOD and GSH were decreased. The results of HE pathological staining showed that liver tissue damage was significantly increased. Compared with model group, ALT and AST levels in serum of compound ALI-57 medium and high dose groups were significantly decreased(P<0.05), the contents of MDA and GDH in liver were significantly decreased(P<0.05), and the activities of SOD and GSH were significantly increased in liver(P<0.05), while there were no significant differences between the low dose group and the model group. CONCLUSION Compound ALI-57 has a significant protective effect on mice with acute liver injury induced by APAP, the mechanism maybe related to reducing oxidative stress and improving antioxidant capacity.