Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo

To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n ‫؍‬ 21) or by plasma concentrations after orally administered digoxin (n ‫؍‬ 8 ؉ 14).We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1.Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels.Homozygosity for this variant was observed in 24% of our sample population (n ‫؍‬ 188).This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.cancer therapy ͉ drug resistance ͉ molecular transport ͉ pharmacogenetics