Epigenetic regulation of genes encoding drug-metabolizing enzymes and transporters; DNA methylation and other mechanisms.
Drug metabolizing enzymes and transporters are increasingly recognized as key determinants of the inter-individual variability in pharmacokinetic (PK) and pharmacodynamic (PD) outcomes of clinically important drugs. To date, most studies investigating this variability have focused on polymorphisms (e.g. SNPs) in the genes encoding metabolic enzymes and transporters; however, it has recently been reported that the expression of some of these genes is under the control of epigenetic mechanisms. The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolizing enzymes and transporter genes.
Hirota
Takeshi
T
Department of Clinical Pharmacokinetics, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Takane
Hiroshi
H
Higuchi
Shun
S
Ieiri
Ichiro
I
D000107:Acetylation; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic
D006657:Histones; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System