Journal
ACTA PHARMACEUTICA SINICA B
Volume 9, Issue 3, Pages 639-647Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2018.12.002
Keywords
Bioengineered RNA; miR-27b; miR-328; CYP3A4; ABCG2; Drug disposition
Categories
Funding
- National Institutes of Health [USA] [R01GM113888]
- Visiting Scholar Programs from China Scholarship Council (USA) [201608440507]
- Guangzhou Medical University (China)
- National Natural Science Foundation of China (China) [81603191]
- Natural Science Foundation of Guangdong Province (China) [2015A030310153]
- Fundamental Research Funds for the Central Universities (China) [3102018zy053]
- UC Davis Comprehensive Cancer Center Support Grant (CCSG) - National Cancer Institute (USA) [P30CA093373]
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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.
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