Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression

Xin Li, Ye Tian, Mei Juan Tu, Pui Yan Ho, Neelu Batra, Aiming Yu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalActa Pharmaceutica Sinica B
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

RNA
Gene Expression
Pharmaceutical Preparations
MicroRNAs
Cytochrome P-450 CYP3A
Adenosine Triphosphate
Bioengineering
Mitoxantrone
Drug and Narcotic Control
Midazolam
Biological Factors
Xenobiotics
Cytoplasmic and Nuclear Receptors
Biotechnology
Mixed Function Oxygenases
Base Pairing
Fermentation
Technology
Drug Therapy
Messenger RNA

Keywords

  • ABCG2
  • Bioengineered RNA
  • CYP3A4
  • Drug disposition
  • miR-27b
  • miR-328

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression. / Li, Xin; Tian, Ye; Tu, Mei Juan; Ho, Pui Yan; Batra, Neelu; Yu, Aiming.

In: Acta Pharmaceutica Sinica B, 01.01.2019.

Research output: Contribution to journalArticle

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AB - 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.

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