RT Journal Article
SR Electronic
T1 Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in the <em>MDR1</em> (<em>ABCB1</em>) Gene
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1179
OP 1187
DO 10.1124/jpet.104.069724
VO 311
IS 3
A1 Hiroshi Takane
A1 Daisuke Kobayashi
A1 Takeshi Hirota
A1 Junzo Kigawa
A1 Naoki Terakawa
A1 Kenji Otsubo
A1 Ichiro Ieiri
YR 2004
UL http://jpet.aspetjournals.org/content/311/3/1179.abstract
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