Effects of Polymorphisms of MDR1, MRP1, and MRP2 Genes on Their mRNA Expression Levels in Duodenal Enterocytes of Healthy Japanese Subjects.

Abstract

In the present study, we examined whether polymorphisms in the ATP-binding cassette (ABC) transporter genes, MDR1, MRP1 and MRP2, were associated with their respective mRNA expression levels in duodenal enterocytes of 13 healthy Japanese volunteers. MDR1 genotypes of T-129C, G2677(A,T) and C3435T, MRP1 genotypes of G128C, C218T, G2168A and G3173A, and MRP2 genotypes of C-24T, G1249A, C2302T, C2366T and G4348A were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or direct sequencing. Mutations T-129C, G2677(A,T) and C3435T of MDRI gene were found at allele frequencies of 2/26, 16/26 and 12/26, respectively. Mutations G2168A of the MRPI gene and C-24T of the MRP2 gene were also found at allele frequencies of 1/26 and 6/26, respectively, whereas other mutations were not detected in MRP1 and MRP2 genes. The relative concentrations (mean +/- S.E.) of MDR1 mRNA to villin mRNA were 0.38 +/- 0.15, 0.56 +/- 0.14 and 1.13 +/- 0.42 in the subjects with C/C3435, C/T(3435) and T/T(3435), respectively, which supported the lower serum concentrations of digoxin after single oral administration in the subjects with the mutant T-allele at position 3435. Genetic collaboration between positions 3435 and 2677 was suggested, and those in G/G2677, G/(A,T)(2677) and T/(A,T)(2677) were 0.16 +/- 0.05, 1.10 +/- 0.40, and 0.63 +/- 0.16, respectively (p = 0.107). However, there was no remarkable effect of the G2168A of the MRP1 gene or of C-24T of the MRP2 gene on the relative MRP1 or MRP2 mRNA concentrations, respectively.