MicroRNA调节CYP 1A2，CYP3A4和CYP2E1对乙酰氨基酚的毒性。,Scientific Reports

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MicroRNA调节CYP 1A2，CYP3A4和CYP2E1对乙酰氨基酚的毒性。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Sep-26 , DOI: 10.1038/s41598-017-11811-y
Pritmohinder Gill , Sudeepa Bhattacharyya , Sandra McCullough , Lynda Letzig , Prasun J. Mishra , Chunqiao Luo , Harsh Dweep , Laura James

在用APAP（20 mM）处理的HepaRG细胞中检查了调节参与对乙酰氨基酚（APAP）毒性的细胞色素P-450亚型的MicroRNA（miRNA）。体外研究发现，APAP蛋白加合物在1 h时增加，而ALT在12和24 h时增加。CYP1A2，CYP3A4和CYP2E1 mRNA水平降低，而miR-122-5p，miR-378a-5p，miR-27b-3p在6h和miR-125b-5p在12h以及miR-27b-3p的miRNA升高。在24小时 CYPs 3'UTR上的推定miRNA结合位点在计算机上得到鉴定。miR-122-5p和miR-378a-5p在细胞中的过表达抑制了CYP1A2，CYP3A4和CYP2E1的蛋白表达。萤光素酶报告基因检测证实了miR-122与CYP1A2和CYP3A4的3'UTR之间的相互作用。因此，体外实验表明，miR-122-5p和miR-378a-5p的上调与CYP的翻译抑制有关。与健康对照相比，过量服用APAP的儿童血清样品中的miR-122-5p，miR-378a-5p，miR-125b-5p和miR-27b-3p显着升高，而miRNA的接收者操作员曲线的AUC为91到100％。总体而言，数据表明，由于细胞应激和损伤，miRNA在APAP毒性中的升高代表调节CYP1A2，CYP3A4和CYP2E1翻译的调节反应。

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MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity.

MicroRNAs (miRNAs) that regulate the cytochrome P-450 isoforms involved in acetaminophen (APAP) toxicity were examined in HepaRG cells treated with APAP (20 mM). In-vitro studies found that APAP protein adducts were increased at 1 h, followed by ALT increases at 12 and 24 h. CYP1A2, CYP3A4 and CYP2E1 mRNA levels were decreased, while miRNAs were increased for miR-122-5p, miR-378a-5p, miR-27b-3p at 6 h and miR-125b-5p at 12 h and miR-27b-3p at 24 h. Putative miRNA binding sites on the 3'UTRs of the CYPs were identified in-silico. Overexpression of miR-122-5p and miR-378a-5p in cells suppressed protein expression of CYP1A2, CYP3A4 and CYP2E1. Luciferase reporter assays confirmed the interaction between miR-122 and the 3'UTR of the CYP1A2 and CYP3A4. Thus, the in-vitro experiments showed that miR-122-5p and miR-378a-5p upregulation were associated with translational repression of CYPs. Serum samples of children with APAP overdose had significant elevation of miR-122-5p, miR-378a-5p, miR-125b-5p and miR-27b-3p, compared to healthy controls and receiver operator curves of the miRNAs had AUCs of 91 to 100%. Collectively, the data suggest that miRNA elevations in APAP toxicity represent a regulatory response to modify CYP1A2, CYP3A4 and CYP2E1 translation due to cellular stress and injury.

更新日期：2017-09-26

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