Relationship between DNA Methylation in the 59 CpG Island of the SLC47A1 (Multidrug and Toxin Extrusion Protein MATE1) Gene and Interindividual Variability in MATE1 Expression in the Human Livers

Toshihiro Tanaka, Takeshi Hirota, Ichiro Ieiri

研究成果: ジャーナルへの寄稿記事

2 引用 (Scopus)

抄録

Multidrug and toxin extrusion protein 1 (MATE1), which is encoded by solute carrier 47A1 (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 this study, we investigated whether DNA methylation was involved in interindividual variability in MATE1 expression in the human liver. Approximately 20-fold interindividual 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 treatment with 5-aza-29-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 59 CpG island of SLC47A1 acts as an enhancer for SLC47A1, and DNA methylation in the CpG island plays an important role in interindividual differences in hepatic MATE1 expression.

元の言語英語
ページ(範囲)1-7
ページ数7
ジャーナルMolecular Pharmacology
93
発行部数1
DOI
出版物ステータス出版済み - 1 1 2018

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CpG Islands
DNA Methylation
Liver
Proteins
Messenger RNA
Deoxycytidine
Hep G2 Cells
Luciferases
Bile
Methylation
Cations
Pharmacokinetics
Urine
Cell Line
DNA

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

これを引用

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abstract = "Multidrug and toxin extrusion protein 1 (MATE1), which is encoded by solute carrier 47A1 (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 this study, we investigated whether DNA methylation was involved in interindividual variability in MATE1 expression in the human liver. Approximately 20-fold interindividual 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 treatment with 5-aza-29-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 59 CpG island of SLC47A1 acts as an enhancer for SLC47A1, and DNA methylation in the CpG island plays an important role in interindividual differences in hepatic MATE1 expression.",
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