title: Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects.
abstract: The effect of the C3435T mutation at exon 26 of the MDR1 gene on the expression levels of MDR1 messenger ribonucleic acid (mRNA) was evaluated by means of real-time polymerase chain reaction in 51 biopsy specimens of duodenum obtained from 13 healthy Japanese subjects. The mRNA levels of MDR1 were 0.38 +/- 0.15, 0.56 +/- 0.14, and 1.13 +/- 0.42 (mean value +/- SE) in the subjects with the homozygote of wild-type allele (C/C), compound heterozygote with mutant T allele (C/T), and the homozygote of the mutant allele (T/T), respectively, reasonably explaining the lower digoxin serum concentration after administration of a single oral dose to subjects harboring a mutant T allele. Good correlation (r =.797; P <.01) was observed between the mRNA concentrations of MDR1 and CYP3A4 in the individual biopsy specimens. This finding suggested a lower plasma concentration of the substrates for CYP3A4 in subjects harboring the C3435T mutation of the MDR1 gene.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Masanori
authors.initials: M
authors.lastname: Horinouchi
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: 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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000483:Alleles; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004077:Digoxin / Q000097:blood; D004386:Duodenum / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020895:Enterocytes / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000097:blood; D005091:Exons / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D024101:Mitochondrial Proteins; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D013941:Thymine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D003596:Cytosine; D004268:DNA-Binding Proteins; D004077:Digoxin; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D006899:Mixed Function Oxygenases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D013941:Thymine; C093947:MRP2 protein, S cerevisiae; C078444:MSH3 protein, human; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human; C421109:multidrug resistance-associated protein 1