Current knowledge of microRNA-mediated regulation of drug metabolism in humans

ABSTRACT

Introduction: Understanding the factors causing inter- and intra-individual differences in drug metabolism potencies is required for the practice of personalized or precision medicine, as well as for the promotion of efficient drug development. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, epigenetic regulation, such as DNA methylation and histone acetylation, and post-translational modification. In addition to such regulation mechanisms, recent studies revealed that microRNAs (miRNAs), endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs, significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes.

Areas covered: This review summarizes the current knowledge regarding miRNAs-dependent regulation of drug-metabolizing enzymes and transcriptional factors and its physiological and clinical significance. We also describe recent advances in miRNA-dependent regulation research, showing that the presence of pseudogenes, single-nucleotide polymorphisms, and RNA editing affects miRNA targeting.

Expert opinion: It is unwavering fact that miRNAs are critical factors causing inter- and intra-individual differences in the expression of drug-metabolizing enzymes. Consideration of miRNA-dependent regulation would be a helpful tool for optimizing personalized and precision medicine.

KEYWORDS:

• Drug metabolism
• CYP
• UGT
• SULT
• microRNA
• post-transcriptional regulation

Article highlights

1. Variability in expression of drug-metabolizing enzymes, such as CYP and UGT, is a critical factor in interindividual differences in drug response and toxicity

2. Some miRNAs down-regulate CYP, UGT, SULT and related transcriptional factors through translational repression or mRNA degradation.

3. Presence of pseudogenes, SNPs, and RNA editing affects the miRNA-dependent regulation of drug metabolizing-enzymes.

4. Elucidation of regulatory mechanisms of miRNA expression in the human livers, focusing on genetic and non-genetic factors, will be useful to understand the causes of inter- or intra-individual variability of drug metabolism potencies.

5. The next challenge is to prove the impact of miRNA-dependent regulation of drug-metabolizing enzymes on pharmacokinetics in vivo.

This box summarizes key points contained in the article.

Declaration of interest

Masataka Nakano supported by Grant-in-Aid for JSPS Fellows from the Japan Society for the Promotion of Science [16J00832]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by Grant-in-Aid for Scientific Research (B) [15H04663] and Grant-in-Aid for JSPS Fellows [16J00832] from the Japan Society for the Promotion of Science.