title: 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.
authors.affiliation: Department of Environmental Biochemistry, Kyoto Pharmaceutical University, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Moriya
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Horinouchi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Takao
authors.initials: T
authors.lastname: Tamura
authors.forename: Nobuo
authors.initials: N
authors.lastname: Aoyama
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Akinobu
authors.initials: A
authors.lastname: Gotoh
authors.forename: Sadaki
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D004386:Duodenum / Q000166:cytology / Q000378:metabolism; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1