The effect of microRNAs in the regulation of human CYP3A4: a systematic study using a mathematical model.
The effect of microRNAs in the regulation of human CYP3A4: a systematic study using a mathematical model.
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microRNA 对人类 CYP3A4 调节的影响：使用数学模型的系统研究
DOI：
10.1038/srep04283
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发表时间：
2014-03-05
影响因子：
4.6
通讯作者：
Xing Q
中科院分区：
文献类型：
--
作者：
Wei Z;Jiang S;Zhang Y;Wang X;Peng X;Meng C;Liu Y;Wang H;Guo L;Qin S;He L;Shao F;Zhang L;Xing Q
CYP 3A 4代谢市场上超过50%的药物。CYP 3A 4表达的巨大个体间差异可能导致人类药物反应的变异性。CYP 3A 4的转录后调控知之甚少，而转录调控已被研究得更彻底。在这项研究中，我们使用多种软件程序来预测可能与CYP 3A 4结合的miRNAs，并确定了112个潜在的功能miRNAs。然后使用荧光素酶报告系统来评估HEK 293 T细胞中每种潜在功能性miRNA的过表达的效果。在人类肝脏样品（N = 27）中测量了14种显著降低报告子活性的miRNA作为候选miRNA。为了建立一种更有效的方法来分析miRNA候选物的体内数据，对功能性miRNA和靶mRNA之间的关系进行了数学建模。利用该模型，我们发现hsa-miR-577、hsa-miR-1、hsa-miR-532- 3 p和hsa-miR-627可显著下调肝脏CYP 3A 4 mRNA的翻译效率。本研究使用计算机模拟、体外和体内方法逐步筛选CYP 3A 4的功能性miRNA，并增强我们对人群中CYP 3A 4表达的个体间差异的分子事件的理解。
CYP3A4 metabolizes more than 50% of the drugs on the market. The large inter-individual differences of CYP3A4 expression may contribute to the variability of human drug responses. Post-transcriptional regulation of CYP3A4 is poorly understood, whereas transcriptional regulation has been studied much more thoroughly. In this study, we used multiple software programs to predict miRNAs that might bind to CYP3A4 and identified 112 potentially functional miRNAs. Then a luciferase reporter system was used to assess the effect of the overexpression of each potentially functional miRNA in HEK 293T cells. Fourteen miRNAs that significantly decreased reporter activity were measured in human liver samples (N = 27) as candidate miRNAs. To establish a more effective way to analyze in vivo data for miRNA candidates, the relationship between functional miRNA and target mRNA was modeled mathematically. Taking advantage of this model, we found that hsa-miR-577, hsa-miR-1, hsa-miR-532-3p and hsa-miR-627 could significantly downregulate the translation efficiency of CYP3A4 mRNA in liver. This study used in silico, in vitro and in vivo methods to progressively screen functional miRNAs for CYP3A4 and to enhance our understanding of molecular events underlying the large inter-individual differences of CYP3A4 expression in human populations.
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影响因子：
14.9
作者：
Kozomara A;Griffiths-Jones S
通讯作者：
Griffiths-Jones S
影响因子：
30.8
作者：
Bentwich, I;Avniel, A;Bentwich, Z
通讯作者：
Bentwich, Z
DOI：
10.1097/00008571-199410000-00003
发表时间：
1994-10-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
KOLARS, JC;LOWN, KS;WATKINS, PB
通讯作者：
WATKINS, PB
影响因子：
15.9
作者：
Lown, KS;Bailey, DG;Watkins, PB
通讯作者：
Watkins, PB
影响因子：
9.8
作者：
John B;Enright AJ;Aravin A;Tuschl T;Sander C;Marks DS
通讯作者：
Marks DS