Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

Abstract

This is a report of a symposium on the potential role of epigenetic mechanisms in the control of drug disposition sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2013 meeting in Boston, MA, April 21, 2013. Epigenetics is a rapidly evolving area, and recent studies have revealed that expression of drug-metabolizing enzymes and transporters is regulated by epigenetic factors, including histone modification, DNA methylation, and noncoding RNAs. The symposium speakers provided an overview of genetic and epigenetic mechanisms underlying variable drug metabolism and drug response, as well as the implications for personalized medicine. Considerable insight into the epigenetic mechanisms in differential regulation of the dioxininducible drug and carcinogen-metabolizing enzymes CYP1A1 and 1B1 was provided. The role of noncoding microRNAs in the control of drug metabolism and disposition through targeting of cytochrome P450 (P450) enzymes and ATP-binding cassette membrane transporters was discussed. In addition, potential effects of xenobiotics on chromatin interactions and epigenomics, as well as the possible role of long noncoding RNAs in regulation of P450s during liver maturation were presented.

Rapid Production of Novel Pre-MicroRNA Agent hsa-mir-27b in Escherichia coli Using Recombinant RNA Technology for Functional Studies in Mammalian Cells

“…In addition, other P450 enzymes (e.g., CYP1B1) and drug transporters (e.g., P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated proteins) may be regulated by miRNAs, such as miR-27b, miR-124, miR-519c, and miR-1291 (Tsuchiya et al, 2006;To et al, 2008;Zhu et al, 2008;Pan et al, 2009bPan et al, , 2013Haenisch et al, 2011;Li et al, 2011;Rieger et al, 2013;Shukla et al, 2013;Xie et al, 2013;Markova and Kroetz, 2014). These findings support the concept that miRNAs are critical epigenetic factors in the modulation of drug metabolism and disposition that might consequently alter drug efficacy (Yu, 2007;Yu and Pan, 2012;Ingelman-Sundberg et al, 2013;Yokoi and Nakajima, 2013).…”

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

“…The rationale for this hypothesis relates to the intersubject variability observed in dogs expressing this mutation (e.g., Mut dogs). Could the remnant of this one gene influence the expression of other genes, or elicit some downstream epigenetic modifications that might normally occur if the gene did not possess a premature stop codon (e.g., Ingelman-Sundberg et al, 2013;Kim et al, 2014)? If this is the case, then much of the work with knockout mice (where the gene is totally removed) could lead to a biased study result, whereby there is an inappropriate loss of ability to identify these "innocent victim" effects of the mutation.…”

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

“…In addition, some genetically modified animal models (Lu et al, 2007;Thai et al, 2007;Xiao et al, 2007;Han et al, 2015) have been developed and used for the examination of specific miRNA targets and functions at the whole organism level. Through the actions of target genes, miRNAs are thus able to control many cellular processes, including ADME, which may subsequently alter drug efficacy and safety profiles (Yu, 2009;Ivanov et al, 2012;Yu and Pan, 2012;Ingelman-Sundberg et al, 2013;Yokoi and Nakajima, 2013;Zhong and Leeder, 2013).…”