TY - JOUR T1 - Relationship between DNA methylation in the 5' CpG island of the <em>SLC47A1</em> (MATE1) gene and inter-individual variability in MATE1 expression in the human liver JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.109553 SP - mol.117.109553 AU - Toshihiro Tanaka AU - Takeshi Hirota AU - Ichiro Ieiri Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/10/25/mol.117.109553.abstract N2 - Multidrug and toxin extrusion protein 1 (MATE1), which is encoded by SLC47A1, mediates the excretion of organic cations into bile and urine. Some genetic variants in human MATE1 altered its transport function in in vitro experiments; however, differences in the pharmacokinetics of substrate drugs cannot be explained by genetic variations in humans. In the present study, we investigated whether DNA methylation was involved in inter-individual variability in MATE1 expression in the human liver. Approximately 20-fold inter-individual variability in MATE1 mRNA expression levels was observed in liver samples and mRNA expression levels negatively correlated with methylation levels of the CpG island in the 27 kb upstream of SLC47A1. DNA demethylation by a treatment with 5-aza-2'-deoxycytidine increased MATE1 mRNA expression in MATE1-negative cell lines. The luciferase reporter assay showed that the CpG island increased the transcriptional activity of the SLC47A1 promoter. MATE1 mRNA expression levels were significantly lower in CpG island knockout HepG2 cells than in control cells. These results suggest that the 5' CpG island of SLC47A1 acts as an enhancer for SLC47A1, and DNA methylation in the CpG island plays an important role in inter-individual differences in hepatic MATE1 expression. ER -