1. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo
- Author
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Ingolf Cascorbi, Ulrich Brinkmann, Sven Hoffmeyer, Oliver Burk, O. von Richter, Ivar Roots, Thomas Gerloff, Eichelbaum Michel, Jürgen Brockmöller, H. P. Arnold, and Andreas Johne
- Subjects
Adult ,Male ,Polymorphism, Genetic ,Multidisciplinary ,Base Sequence ,biology ,ATP-binding cassette transporter ,DNA ,Exons ,Biological Sciences ,Molecular biology ,Exon ,In vivo ,Polymorphism (computer science) ,Sequence Homology, Nucleic Acid ,biology.protein ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Intestinal Mucosa ,Allele ,CYP3A5 ,Gene ,Alleles ,P-glycoprotein - Abstract
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.
- Published
- 2000
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