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 co rrelate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PCP) substrates, we analyzed the MDR-1 sequence in 21 volun teers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma co ncentrations 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 p olymorphism had significantly lower duodenal MDR-1 expression and the highe st digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affec t the absorption and tissue concentrations of numerous other substrates of MDR-1.