对乙酰氨基酚致大鼠肝损伤早期生物标志物水平的变化规律

Dynamic Changes of Biomarker Levels in Early Stage of Acetaminophen-induced Liver Injury

目的:通过比较对乙酰氨基酚(APAP)致肝损伤模型大鼠传统生物标志物丙氨酸氨基转移酶(ALT),天冬氨酸氨基转移酶(AST),碱性磷酸酶(ALP),总胆红素(TBIL)和潜在生物标志物谷氨酸脱氢酶(GLDH),嘌呤核苷酸磷酸化酶(PNP),α-谷胱甘肽-S-转移酶(α-GST),精氨酸酶1(Arg1)的变化来判断GLDH,PNP,α-GST,Arg1是否可以作为检测药物性肝损伤的早期生物标志物。方法:48只大鼠随机分为2组,分为正常组、模型组,每组24只,雌雄各半。给予模型组灌胃1 250 mg·kg^-1APAP溶液复制药物性肝损伤的模型,在给予APAP后3,6,12,24 h,每个时间点每组随机取6只大鼠(雌雄各半),检测血清ALT,AST,ALP,TBIL,GLDH,PNP,α-GST,Arg1水平及肝组织匀浆GLDH,PNP,α-GST,Arg1水平;苏木素-伊红(HE)染色检查肝组织病理学变化。结果:与正常组比较,模型组大鼠血清和肝组织匀浆的ALT,AST,ALP,TBIL,GLDH,PNP,α-GST,Arg1水平均明显升高(P <0. 05,P <0. 01),表明APAP致药物性肝损伤模型复制成功。模型组大鼠血清和肝组织的GLDH,PNP,α-GST,Arg1水平比ALT,AST水平升高时间早,幅度大。结论:GLDH,PNP,α-GST,Arg1较传统肝功能检测指标具有较好的灵敏性,可以作为早期检测药物性肝损伤的生物标志物。

Objective: To determine whether glutathione dehydrogenase( GLDH),purine nucleotide phosphorylase( PNP),α-glutathione-S-transferase( α-GST),and arginase 1( Arg1) can be used as the early biomarkers of drug-induced liver injury by comparing the changes of traditional biomarkers alanine aminotransferase( ALT),aspartate aminotransferase( AST) and alkaline phosphatase( ALP),total bilirubin( TBIL) and potential biomarkers GLDH,PNP,α-GST and Arg1 in acetaminophen( APAP)-induced liver injury model rats. Method:The 48 rats were randomly divided into two groups: blank group and model group. 24 rats in each group,half male and half female. The model group received 1 250 mg·kg^-1APAP solution by intragastric administration to establish the drug-induced liver injury. 6 rats( half male and half female) were randomly selected from each group at 3,6,12 and 24 h after APAP was given to the model group,to detect the levels of ALT,AST,ALP,TBIL,GLDH,PNP,α-GST,Arg1 in serum and levels of GLDH,PNP,α-GST,Arg1 in liver tissue homogenate at each time point Histopathological changes of liver tissues were observed by hematoxylin-eosin( HE) staining. Result: As compared with the blank group,the levels of ALT,AST,ALP,TBIL,GLDH,PNP,α-GST and Arg1 in serum and liver homogenates were significantly increased in model group( P < 0. 05,P < 0. 01),indicating that the APAP-induced liver injury model was successfully replicated. GLDH,PNP,α-GST and Arg1 levels in serum and liver tissues of rats in the model group were increased earlier and more significantly than ALT and AST levels.Conclusion: GLDH,PNP,α-GST and Arg1 can be used as biomarkers for early detection of drug-induced liver injury.