Short communication
Xin Li, Ye Tian, Mei-Juan Tu, Pui Yan Ho, Neelu Batra, Ai-Ming Yu. Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 639-647

Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression
Xin Lia,c, Ye Tianb,c, Mei-Juan Tuc, Pui Yan Hoc, Neelu Batrac, Ai-Ming Yuc
a Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China;
b Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China;
c Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
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.
Key words:    Bioengineered RNA    miR-27b    miR-328    CYP3A4    ABCG2    Drug disposition   
Received: 2018-10-03     Revised:
DOI: 10.1016/j.apsb.2018.12.002
Funds: This work was supported in part by the National Institutes of Health[Grant No. R01GM113888 (Aiming Yu), USA]. Xin Li was supported by Visiting Scholar Programs from China Scholarship Council (201608440507, USA) and Guangzhou Medical University, National Natural Science Foundation of China (81603191, China) and Natural Science Foundation of Guangdong Province (2015A030310153, China). Ye Tian was supported by the 3102018zy053 from Fundamental Research Funds for the Central Universities (China). The authors appreciate the access to the Flow Cytometry and Molecular Pharmacology Shared Resources funded by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (Grant No. P30CA093373, USA).
Corresponding author: Ai-Ming Yu
Author description:
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Xin Li
Ye Tian
Mei-Juan Tu
Pui Yan Ho
Neelu Batra
Ai-Ming Yu

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