Proceedings of the National Academy of Sciences · 2000 · 2.4K citations · 32 references
MedicineMolecular GeneticsPharmacologyMolecular PharmacologyPharmacogeneticsPharmacogenomicsDrug DispositionDrug Metabolism GeneticsDrug Transporter GeneticsMultidrug ResistanceReceptor PolymorphismsDrug Metabolism PolymorphismsIntestinal Drug Transporter GeneticsPharmacokinetics Of Transporter VariantsProtein Expression LevelsResistance Gene Polymorphism AnalysisTransporter Gene PolymorphismsTransporter Polymorphism Effects
The C3435T polymorphism in MDR‑1 is expected to influence absorption and tissue concentrations of many MDR‑1 substrates. The study aimed to determine whether MDR‑1 sequence variations correlate with intestinal MDR‑1 expression and oral P‑glycoprotein substrate uptake. Researchers genotyped 21 volunteers and measured duodenal MDR‑1 expression by Western blot and immunohistology or assessed digoxin plasma levels after oral administration. A significant association was found between the exon 26 C3435T variant and lower duodenal MDR‑1 expression, higher digoxin plasma concentrations, with homozygotes representing 24 % of the cohort.
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.
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