PT - JOURNAL ARTICLE AU - Hiroshi Takane AU - Daisuke Kobayashi AU - Takeshi Hirota AU - Junzo Kigawa AU - Naoki Terakawa AU - Kenji Otsubo AU - Ichiro Ieiri TI - Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in the <em>MDR1</em> (<em>ABCB1</em>) Gene AID - 10.1124/jpet.104.069724 DP - 2004 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1179--1187 VI - 311 IP - 3 4099 - http://jpet.aspetjournals.org/content/311/3/1179.short 4100 - http://jpet.aspetjournals.org/content/311/3/1179.full SO - J Pharmacol Exp Ther2004 Dec 01; 311 AB - 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. The American Society for Pharmacology and Experimental Therapeutics