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.
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.
Nakamura
Tsutomu
T
Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
Sakaeda
Toshiyuki
T
Horinouchi
Masanori
M
Tamura
Takao
T
Aoyama
Nobuo
N
Shirakawa
Toshiro
T
Matsuo
Masafumi
M
Kasuga
Masato
M
Okumura
Katsuhiko
K
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
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