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

Clin Pharmacol Ther. 2002 Apr;71(4):297-303. doi: 10.1067/mcp.2002.122055.

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Alleles
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics
  • Cytosine / metabolism
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Digoxin / blood
  • Duodenum / cytology
  • Duodenum / enzymology
  • Duodenum / metabolism*
  • Enterocytes / enzymology
  • Enterocytes / metabolism*
  • Enzyme Inhibitors / blood
  • Exons / genetics*
  • Gene Expression Regulation / genetics*
  • Genes, MDR / genetics*
  • Humans
  • Japan
  • Male
  • Mitochondrial Proteins*
  • Mixed Function Oxygenases / biosynthesis
  • Mixed Function Oxygenases / genetics
  • Multidrug Resistance-Associated Proteins*
  • MutS Homolog 3 Protein
  • Mutation / genetics*
  • RNA, Messenger / biosynthesis*
  • RNA, Messenger / genetics
  • Ribosomal Proteins / biosynthesis
  • Ribosomal Proteins / genetics
  • Saccharomyces cerevisiae Proteins*
  • Thymine / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • MRP2 protein, S cerevisiae
  • MSH3 protein, human
  • Mitochondrial Proteins
  • Multidrug Resistance-Associated Proteins
  • MutS Homolog 3 Protein
  • RNA, Messenger
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins
  • Digoxin
  • Cytosine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Thymine
  • multidrug resistance-associated protein 1