Epigenetic regulation of drug transporter expression in human tissues

ABSTRACT

Introduction: Drug transporters are expressed in a number of tissues such as the intestine, liver, and kidney, and play key roles in drug absorption, distribution, and excretion. Variations in drug transporter gene expression significantly contribute to interindividual differences in drug responses. Epigenetic regulation of drug transporter genes has recently emerged as an important mechanism. Epigenetic regulation alters the expression of genes without changing DNA sequences. Epigenetic control mechanisms are associated with DNA methylation, histone modifications, and microRNAs. Herein we discuss recent advances in the study of the transcriptional and post-transcriptional mechanisms of drug transporters with a focus on epigenetic regulation.

Areas covered: This review summarizes recent research on the epigenetic regulation of drug transporter genes, and highlights the importance of identifying novel biomarkers based on epigenetics for use in individualized drug therapy.

Expert opinion: Researchers are actively attempting to elucidate the epigenetic mechanisms that control the expression of drug transporters, which affect the pharmacokinetics of drugs. Current evidence suggests that epigenetic changes play an important role in drug transporter function. A clearer understanding of epigenetic regulation in drug transporter genes will provide an insight into novel approaches to individualized drug therapy.

KEYWORDS:

• Drug transporters
• epigenetics
• DNA methylation
• histone modifications
• microRNA

Article highlights

• It is important to clarify the contribution of DNA methylation to individual variability, based on the mechanisms responsible for the regulation of drug transporter expression by DNA methylation.

• The contribution of histone modifications to inter-individual differences in the expression of drug transporters, except for SLC22A2 has not yet been investigated.

• Not only SNPs, but also DNA methylation in the promoter region of miRNA may play an important role in the inter-individual differences in miRNA expression and the functions of miRNA-targeted drug transporter genes.

• The incorporation of epigenetic variations into DNA sequence variations may provide an insight into new approaches to individualized drug therapy.

• The establishment of specific isolation and normalization strategies is needed for individualized drug therapy by using novel epigenetic biomarkers.

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Declaration of interest

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.

Additional information

Funding

This work was supported by JSPS KAKENHI Grant Number 26460199.