血清miR-122作为药物肝损伤生物标志物的敏感性和特异性比较

发布时间：2018-12-28 21:23

【摘要】：目的比较研究血清微RNA-122(miR-122)作为药物肝损伤生物标志物的敏感性和特异性,为miR-122用于早期药物肝毒性评价提供依据。方法采用对乙酰氨基酚(APAP,1250 mg·kg~(-1),ig)、α-萘异硫氰酸酯(ANIT,150 mg·kg~(-1),ig)、蛋氨酸-胆碱缺乏饮食(MCDD,自由摄食)以及四氯化碳(CCI_4,50%,ip)分别制备大鼠肝细胞损伤模型、胆汁淤积模型、脂肪肝模型以及肝纤维化模型,用于评价miR-122作为药物肝损伤生物标志物的敏感性。采用盐酸异丙肾上腺素(IH,2.5 mg·kg~(-1),iv)和庆大霉素(GM,80 mg·kg~(-1),im)分别制备大鼠心肌损伤模型和肾损伤模型,用于评价miR-122作为药物肝损伤生物标志物的特异性于不同时间点采集大鼠血清和肝组织,采用全自动生化仪检测血清谷丙转氨酶(GPT)和谷草转氨酶(GOT)活性及总胆红素(TBIL)浓度,采用实时定量PCR检测血清miR-122,并采用HE染色对肝组织进行组织病理检查。结果与溶媒对照组相比,肝细胞损伤模型、胆汁淤积模型、脂肪肝模型和肝纤维化模型组血清miR-122明显升高(2倍)的时间分别为给药后1.5 h,3 h,2周和4周,均早于传统生物标志物GPT,GOT和TBIL[给药后6 h,12 h,3周和6周均未见明显升高(2倍)],同时其升高幅度(最大升高倍数分别为235.8,202.7,73.8和600.3倍)也高于传统生物标志物GPT,GOT和TBIL(GPT最大升高倍数分别为9.5,3.9,2.5和6.6倍,GOT为6.0,2.4,1.4和3.5倍,TBIL为2.6,2.3,1.2和1.8倍)在心肌损伤模型中,GOT活性明显升高(2.1倍),而血清miR-122无明显改变;在肾损伤模型中,血清miR-122无明显改变。结论血清mi R-122可作为药物肝损伤生物标志物,且与传统肝损伤生物标志物如GPT,GOT和TBIL相比有更高的敏感性和特异性。
[Abstract]:Objective to compare the sensitivity and specificity of serum microRNA-122 (miR-122) as a biomarker of liver injury and to provide evidence for the evaluation of liver toxicity by miR-122. Methods APAP,1250 mg kg~ (-1), ig), 伪 -naphthaleneisothiocyanate) (ANIT,150 mg kg~ (-1), ig), methionine choline deficiency) diet (MCDD,) was used. Rat liver cell injury model, cholestasis model, fatty liver model and hepatic fibrosis model were established by free ingestion) and carbon tetrachloride (CCI_4,50%,ip), respectively. To evaluate the sensitivity of miR-122 as a biomarker for liver injury. Myocardial injury model and renal injury model were established by IH,2.5 mg kg~ (-1), iv) and GM,80 mg kg~ (-1), im), respectively. To evaluate the specificity of miR-122 as a biomarker of drug liver injury, serum and liver tissues were collected from rats at different time points. The activities of serum alanine aminotransferase (GPT), glutamic oxalacetic transaminase (GOT) and total bilirubin (TBIL) were detected by automatic biochemical instrument. The serum miR-122, was detected by real-time quantitative PCR and the liver tissue was examined by HE staining. Results compared with the control group, the time of serum miR-122 in hepatocyte injury model, cholestasis model, fatty liver model and hepatic fibrosis group was 2 times higher than that in the control group. Both of them were earlier than the traditional biomarkers GPT,GOT and TBIL [no significant increase (2 times) was found at 6 h after administration at 3 and 6 weeks]. At the same time, the range of increase (the maximum rise times were 235.8202.7 and 600.3 times respectively) was also higher than that of the traditional biomarkers GPT,GOT and TBIL (GPT, which were 9.5U 3.9U 2.5 and 6.6 times, respectively. In myocardial injury model, the activity of GOT increased significantly (2.1fold), but the serum miR-122 did not change significantly. There was no significant change in serum miR-122 in renal injury model. Conclusion Serum mi R-122 can be used as biomarker of liver injury, and it is more sensitive and specific than traditional biomarkers such as GPT,GOT and TBIL.
【作者单位】：西北工业大学生命学院;中国医药工业研究总院国家上海新药安全评价研究中心;
【基金】：国家自然科学基金(81273603) 上海市青年科技启明星计划(14QB1400400) 上海科委实验动物专项基金(14140900900)~~
【分类号】：R965

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