Systematic screening of human ABCC3 polymorphisms and their effects on MRP3 expression and function

Tomohiro Sasaki, Takeshi Hirota, Yuriko Ryokai, Daisuke Kobayashi, Miyuki Kimura, Shin Irie, Shun Higuchi, Ichiro Ieiri

研究成果: ジャーナルへの寄稿記事

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The present study was undertaken to identify genetic polymorphisms of multidrug resistanceassociatedprotein 3 (MRP3, gene name ABCC3), an ATP-binding cassette transporter that mediates thetransport of substrates across the basolateral membrane into the blood, and to investigate their effects onABCC3 expression and MRP3 function. We identified genetic polymorphisms of ABCC3 and evaluatedthe effects by (1) a luciferase reporter gene assay, (2) measuring mRNA levels, and (3) a humanpharmacogenomics study with 4-methylumbelliferone glucuronide (4-MUG). Overall, 61 genetic variantswere identified in three ethnic populations; of these variants 17 were novel (7 were non-synonymous:61Arg>Cys, 132Gln>Stop, 221Trp>Stop, 270His>Gln, 548Leu>Gln, 600Lys>Arg, and 1324Arg>His). However, these mutations occurred at very low frequencies (max. 4.7%). The observed allelefrequencies showed considerable inter-ethnic differences. The reporter gene assay indicated a significantreduction of transcriptional activity with the - 1767G>A allele compared to the wild-type allele; however, adecreased expression of ABCC3 mRNA was not detected in human liver samples. A human pharmacokineticstudy showed that the ABCC3 genotype in the promoter region was not associated with changes inthe pharmacokinetics of 4-MUG, a substrate of MRP3. This is the first study to assess the effects of ABCC3polymorphisms on human pharmacokinetics; however, further investigations are needed to complete thepicture.

元の言語英語
ページ(範囲)374-386
ページ数13
ジャーナルDrug metabolism and pharmacokinetics
26
発行部数4
DOI
出版物ステータス出版済み - 1 1 2011

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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