Small interfering RNA in drug metabolism and transport.
RNA interference (RNAi) is a powerful technique that utilizes RNA molecules to specifically knock down the expression of targeted gene at posttranscriptional level. These small interfering RNAs (siRNAs) not only have broad application to basic biomedical research but may be developed as therapeutic agents. Drug-metabolizing enzymes (DMEs) and drug transporters (DTs) are molecular determinants of pharmacokinetic property of a drug. Transcriptional gene expression of DMEs and DTs is controlled by xenobiotic-sensing nuclear receptors (NRs). Because of complexity in studying the function of individual DMEs, DTs and NRs, siRNAs can be an excellent addition to chemical inhibitors and inhibitory antibodies in delineating their specific roles in drug metabolism and transport, gene regulation, and drug-drug interactions. RNAi may be employed to modulate DT expression to overcome multidrug resistance. Recent studies using RNAi to silence gene expression of specific DME, DT and NR, and the impact on drug metabolism and transport are discussed in this review. Concerns remain about the efficiency, specificity, and off-target effects when interpreting data obtained from RNAi studies. Furthermore, potential role for endogenous siRNAs, microRNA (miRNA) molecules, in controlling the posttranscriptional gene regulation of DMEs, DTs and NRs is discussed.
Yu
Ai-Ming
AM
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. aimingyu@buffalo.edu
D000284:Administration, Oral; D001692:Biological Transport; D001711:Biotransformation; D005786:Gene Expression Regulation; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D034741:RNA, Small Interfering