Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression
Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression
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生物工程化的 miR-27b-3p 和 miR-328-3p 通过调节靶 ADME 基因表达来调节药物代谢和处置
DOI：
10.1016/j.apsb.2018.12.002
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发表时间：
2019-05-01
影响因子：
14.5
通讯作者：
Yu, Ai-Ming
中科院分区：
文献类型：
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作者：
Li, Xin;Tian, Ye;Yu, Ai-Ming
药物代谢酶、转运体和核受体对于药物和外源物质的吸收、分布、代谢和排泄(ADME)是必不可少的。MicroRNAs通过与靶转录本不完全互补的Watson Crick碱基对参与ADME基因表达的调控。细胞色素P450 3A4(CYP3A4)和三磷酸腺苷结合盒G亚家族成员2(ABCG2)分别受miR-27b-3p和miR-328-3p调控。在这里，我们利用我们新建立的RNA生物工程技术，通过发酵生产生物工程RNA制剂(BERA/miR-27B-3P和BERA/miR-328-3P)。与载体或对照RNA处理的细胞相比，Bera/miR-27b-3p和Bera/miR-328-3p被选择性地作用于miRNAs，从而分别下调了CYP3A4和ABCG2的mRNA及其蛋白水平。因此，Bera/miR-27b-3p导致咪达唑仑1‘-羟基酶活性降低，表明细胞色素P3A4活性降低。同样，Bera/miR-328-3p处理增加了抗癌药物米托蒽醌(ABCG2的经典底物)在细胞内的积聚，从而使细胞对化疗敏感。这些结果表明，利用RNA生物技术制备的生物miRNA制剂可以应用于研究miRNA在药物代谢和处置调节中的功能，为开发更有效的治疗方法提供依据。(三)2019年中国医药学会、中国医学科学院药物所。爱思唯尔B.V.制作和主办。
Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion (ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression via imperfect complementary Watson Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette sub-family G member 2 (ABCG2) are regulated by miR-27b-3p and miR-328-3p, respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, via fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down CYP3A4 and ABCG2 mRNA and their protein levels, respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 1'-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise, BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.