Ai-Ming Yu1. 1. University at Buffalo, The State University of New York, School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Buffalo, NY 14260-1200, USA. aimingyu@buffalo.edu
Abstract
BACKGROUND: 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. OBJECTIVE: 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.
BACKGROUND: 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. OBJECTIVE: 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.
Authors: Dianke Yu; Bridgett Green; William H Tolleson; Yaqiong Jin; Nan Mei; Yongli Guo; Helen Deng; Igor Pogribny; Baitang Ning Journal: Biochem Pharmacol Date: 2015-08-19 Impact factor: 5.858