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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 27, 2004; DOI: 10.1124/jpet.104.069724

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Received for publication April 15, 2004.
Revised July 26, 2004.
Accepted for publication July 27, 2004.

Haplotype-oriented genetic analysis and functional assessment of promoter variants in the MDR1 (ABCB1) gene

Hiroshi Takane 1*, Daisuke Kobayashi 2, Takeshi Hirota 2, Junzo Kigawa 3, Naoki Terakawa 3, Kenji Otsubo 1, Ichiro Ieiri 1

1 Department of Hospital Pharmacy, Faculty of Medicine, Tottori University 2 Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University 3 Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University

* Address correspondence to: E-mail: takane{at}grape.med.tottori-u.ac.jp

Abstract

Recently, a number of nucleotide variants have been described in the multidrug resistance 1 (MDR1/ABCB1) gene; however most studies have focused on the coding region. In the present study, we identified promoter variants of the MDR1 gene, and evaluated their phenotypic consequences using a reporter gene assay and the real-time PCR method. Ten allelic variants were detected in the promoter region (approx. 2 kb), seven of which were newly identified. Certain mutations occurred simultaneously, and a total of ten haplotypes were observed. These promoter polymorphisms were found more frequently in Japanese than Caucasians. Some haplotypes were associated with changes in luciferase activity, and placental and hepatic mRNA levels. We also determined DNA methylation status in the proximal promoter region of the MDR1 gene. The promoter region around potential binding sites for transcription factors was found to be hypomethylated, and thus likely to be independent of the gene expression. Nucleotide and/or haplotype variants not only in the coding region but also in the promoter region of the MDR1 gene may be important for interindividual differences of P-glycoprotein expression.


Key words: DNA methylation, MDR1, genetic polymorphisms, haplotypes, promoter region, transporter


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