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

2000; National Academy of Sciences; Volume: 97; Issue: 7 Linguagem: Inglês

10.1073/pnas.97.7.3473

1091-6490

Sven Hoffmeyer, Oliver Burk, Oliver von Richter, Hannes Arnold, J. Brockmöller, Andreas Johne, Ingolf Cascorbi, Thomas Gerloff, Ivar Roots, Michel Eichelbaum, Ulrich Brinkmann,

Pediatric Hepatobiliary Diseases and Treatments

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.