University at Buffalo, The State University of New York, School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Buffalo, NY 14260-1200, USA.
Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1513-28. doi: 10.1517/17425250903307448.
The important role of nuclear receptors in transcriptional gene regulation of drug-metabolizing enzymes (DMEs) and drug transporters (DTs) has been well documented. In contrast, there is limited understanding of post-transcriptional gene regulation of DMEs and DTs. MicroRNAs (miRNAs) represent a large group of non-coding RNAs that control the post-transcriptional expression of target genes. Currently, > 800 miRNAs have been identified in human genome, which are believed to regulate thousands of human protein-coding genes.
This review aims to discuss the potential role of miRNAs in drug metabolism and disposition, following an introduction of miRNA biogenesis, regulatory mechanisms, and target identification and validation.
RESULTS/CONCLUSIONS: Some miRNAs have been shown to directly or indirectly control the expression of DMEs, DTs or nuclear receptors, and consequently, affect the capacity of drug metabolism and disposition, and influence the sensitivity of cells to xenobiotic agents. Furthermore, the expression of some miRNAs is readily altered in cells after an acute or chronic exposure to medications, toxins or carcinogens. Therefore, dysregulation of specific miRNAs by a xenobiotic agent, which control the expression of DMEs or DTs, might lead to considerable change in the pharmacokinetic and pharmacodynamic property of a concomitant drug or the agent itself. Improved understanding of the regulatory pathways of DMEs and DTs shall provide novel insight into multi-drug resistance and potential drug-drug interaction in clinical pharmacotherapy as well as in drug discovery and development.
核受体在药物代谢酶（DMEs）和药物转运体（DTs）的转录基因调控中起着重要作用，这一点已得到充分证实。相比之下，人们对 DMEs 和 DTs 的转录后基因调控知之甚少。microRNAs（miRNAs）是一大类非编码 RNA，可控制靶基因的转录后表达。目前，人类基因组中已鉴定出超过 800 种 miRNAs，据信它们可调控数千个人类蛋白编码基因。
本综述旨在讨论 miRNA 在药物代谢和处置中的潜在作用，首先介绍 miRNA 的生物发生、调控机制以及靶基因的鉴定和验证。
结果/结论：一些 miRNA 已被证明可直接或间接控制 DMEs、DTs 或核受体的表达，从而影响药物代谢和处置能力，并影响细胞对外源化合物的敏感性。此外，某些 miRNA 的表达在细胞受到药物、毒素或致癌物的急性或慢性暴露后很容易发生改变。因此，外源化合物对控制 DMEs 或 DTs 表达的特定 miRNA 的失调可能导致伴随药物或药物本身的药代动力学和药效学特性发生重大变化。对 DMEs 和 DTs 调控途径的深入了解将为临床药理学中的多药耐药性和潜在药物相互作用以及药物发现和开发提供新的思路。
