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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in the MDR1 (ABCB1) Gene

Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan (H.T., K.O., I.I.); Department of Clinical Pharmacology, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Fukuoka, Japan (D.K.); Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Fukuoka, Japan (T.H.); and Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University, Yonago, Japan (J.K., N.T.)

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 polymerase chain reaction method. Ten allelic variants were detected in the promoter region (approximately 2 kilobases), seven of which were newly identified. Certain mutations occurred simultaneously, and a total of 10 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.

Address correspondence to: Dr. Hiroshi Takane, Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, 36-1, Nishi-machi, Yonago, 683-8504, Japan. E-mail: takane{at}grape.med.tottori-u.ac.jp

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