ABCMdb

PMID: 12392094

Moriya Y, Nakamura T, Horinouchi M, Sakaeda T, Tamura T, Aoyama N, Shirakawa T, Gotoh A, Fujimoto S, Matsuo M, Kasuga M, Okumura K
Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects.
Biol Pharm Bull. 2002 Oct;25(10):1356-9., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCB1 p.Gly1249Ala The small intestine is the primary site of absorption for many drugs administered orally, and P-glycoprotein (MDR1) located in the villus epithelium of the small intestine is considered to play a role in limiting the absorption of xenobiotics.1,2) The extrusive function of the multidrug resistance-associated proteins (MRPs) have also attracted a great deal of attention in the small intestine.3) MDR1, MRP1 and MRP2 have been reported to show genetic polymorphisms,4-8) and their genotypes are thought to be responsible for the inter-individual differences in absorption properties of the drugs that are their substrates.6,9,10) Kim et al. reported that plasma concentration of fexofenadine after single oral administration was lower in subjects homozygous for the mutant allele at exon 26, position 3435 of the MDR1 gene (T/T3435 ), than in those homozygous for the wild-type allele (C/C3435 ).9) We also demonstrated that systemic exposure to digoxin after single oral administration was lower in subjects with the mutation C3435T of the MDR1 gene.10) C3435T is a silent mutation without amino acid substitution, and its effects on phenotype have been discussed from the viewpoint of changes in the level of expression rather than changes in the function of MDR1.6,11) Thus, in the present study, the effects of the 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 on their mRNA expression levels were examined in human duodenal enterocytes obtained from 13 healthy male Japanese subjects. Login to comment 14 ABCB1 p.Gly1249Ala 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. Login to comment 28 ABCB1 p.Gly1249Ala MDR1, MRP1 and MRP2 Genotyping Genomic DNA was extracted by the method described previously.10) In the present study, the mutation T-129C in the promoter region, 1 missence mutation (G2677(A,T)) and 1 silent mutation (C3435T) in the MDR1 gene, 4 missense mutations (G128C, C218T, G2168A and G3173A) in the MRP1 gene and 4 missense mutations (G1249A, C2302T, C2366T and G4348A) and the mutation C-24T in the 5Ј-flankling region in the MRP2 gene were examined. Login to comment 46 ABCC1 p.Ala893Ser ABCC1 p.Ala893Thr These results suggested that the higher MDR1 expression in the duodenum was associated with the lower plasma concentration of fexofenadine and serum concentration of digoxin after single oral administration in subjects with the mutant T-allele at position 3435.9,10) The silent mutation C3435T has been suggested to be linked with the missense G2677(A,T) producing Ala893Thr and Ala893Ser, respectively.9,11) In the present study, the mutations T-129C, G2677(A,T) and C3435T of the MDR1 gene were found at allele frequencies of 2/26, 16/26 and 12/26, respectively, and 3 of 5 subjects with C/C3435 were accompanied with G/G2677 , and 3 of 4 subjects with T/T3435 were accompanied with T/T2677 , probably due to linkage between positions 3435 and 2677 in the MDR1 gene (Table 1). Login to comment 53 ABCB1 p.Gly1249Ala Among the mutations C-24T, G1249A, C2302T, C2366T and G4348A in the MRP2 gene, only C-24T was detected in the 13 subjects in the present study, and 61% (8/13) were homozygous for the wild-type allele (C/C-24 ), 31% (4/13) were compound heterozygotes (C/T-24 ), and only one subject (1/13, 8%) was homozygous for the mutant allele (T/T-24 ) (Table 1). Login to comment