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. 2012 Apr;2(2):93-101.
doi: 10.1016/j.apsb.2012.02.011. Epub 2012 Mar 31.

Noncoding microRNAs: small RNAs play a big role in regulation of ADME?

Ai-Ming Yu  1 , Yu-Zhuo Pan  1
Affiliations

Noncoding microRNAs: small RNAs play a big role in regulation of ADME?

Ai-Ming Yu et al. Acta Pharm Sin B. 2012 Apr.

Abstract

There are considerable interindividual variations in drug absorption, distribution, metabolism and excretion (ADME) in humans, which may lead to undesired drug effects in pharmacotherapy. Some of the mechanistic causes are known, e.g., genetic polymorphism, inhibition and induction of ADME enzymes and transporters, while others such as posttranscriptional regulation of ADME genes are under active study. MicroRNAs (miRNAs) are a large group of small, noncoding RNAs that control posttranscriptional expression of _target genes. More than 1000 miRNAs have been identified in the human genome, which may regulate thousands of protein-coding genes. Some miRNAs directly or indirectly control the expression of xenobiotic-metabolizing cytochrome P450 enzymes, ATP-binding cassette or solute carrier transporters and/or nuclear receptors. Consequently, intervention of miRNA epigenetic signaling may alter ADME gene expression, change the capacity of drug metabolism and transport, and influence the sensitivity of cells to xenobiotics. In addition, the expression of some ADME regulatory miRNAs is significantly changed in cells following the exposure to a given drug, and the consequent changes in ADME gene expression might result in distinct ADME properties and drug response. In this review, we summarized recent findings on the role of noncoding miRNAs in epigenetic regulation of ADME genes and discussed the potential impact on pharmacokinetics and pharmacodynamics.

Keywords: Cancer; Epigenetics; Gene regulation; MicroRNA; Multidrug resistance; Pharmacokinetics.

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Figures

Figure 1
Figure 1
Xenobiotic-metabolizing enzymes and transporters underlying drug absorption, distribution, metabolism and excretion processes are regulated at the transcriptional, posttranscriptional and posttranslational levels. Different extents of ADME gene expression may result in considerable variations in pharmacokinetics and pharmacodynamics.
Figure 2
Figure 2
(A) One microRNA (e.g., miR-27b) may regulate the expression of an ADME gene via direct _targeting the gene (e.g., CYP3A4) and/or “indirect” _targeting its regulatory factors (e.g., PPARα/NR1C1, PPARγ/NR1C3, VDR/NR1I1 and RXRα/NR2B1). (B) Multiple microRNAs (e.g., miR-520h, −519c and −328) can _target the same ADME gene (e.g., BCRP/ABCG2).
Figure 3
Figure 3
Change in the expression/maturation of ADME gene regulatory miRNAs by a drug may alter the expression of drug-metabolizing enzymes and/or transporters, resulting in a variable drug exposure and drug response.
See this image and copyright information in PMC

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