Received for publication October 12, 2005.
Revised April 9, 2006.
Accepted for publication April 11, 2006.

The promoter region of the MDR1 gene is largely invariant but different SNP-haplotypes affect MDR1 promoter activity differently in different cell-lines

Abstract

The MDR1 multidrug transporter represents one of the better characterized drug transporters that play an important role in protecting the body against xenobiotic insults. Single nucleotide polymorphisms (SNPs) and SNP-haplotypes within this gene have been variously associated with differences in MDR1 expression/function, drug response as well as disease susceptibility. Nonetheless, the effect of polymorphisms at the MDR1 promoter region on its promoter activity remains less characterized. Through the examination of ~1.5kb of MDR1 promoter region from five populations including the Chinese, Malays, Indians, European-Americans and African-Americans, we identified 8 low-frequency SNPs, of which only two were polymorphic in at least four of the five populations examined. The other SNPs are mainly population-specific, majority of which occur only in the African-American population. Recapitulation of the various combinations of SNP haplotypes in vitro in promoter-reporter assays revealed a few notable trends. The African- and European-American-specific haplotypes tended to result in enhanced MDR1 promoter activity only in the HEK293 human embryonic kidney cell-line. Haplotype GCTAACC, which occur at variable frequencies in all the populations examined, with Asians having much lower frequencies (<2%) compared to the European-American/African-Americans (>4%), affected MDR1 promoter activity differently in different cell-lines. Compared to the commonest haplotype, GCTAACC haplotype resulted in a significant decrease in MDR1 promoter activity in HeLa cells (P<0.05) but a significant increase in the same promoter activity in HEK293 cells (P<0.05). These results suggest that the MDR1 promoter region is largely invariant but different haplotypes have differential effects on the MDR1 promoter activity in different cell-lines.

Key words: Promoter analysis, MDR/p-Glycoprotein

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