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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Expression of P-glycoprotein in Human Placenta: Relation to Genetic Polymorphism of the Multidrug Resistance (MDR)-1 Gene

Mizuho Tanabe, Ichiro Ieiri, Naoki Nagata, Kazuko Inoue, Soichiro Ito, Yasunobu Kanamori, Masakuni Takahashi, Yasuo Kurata, Junzo Kigawa, Shun Higuchi, Naoki Terakawa and Kenji Otsubo
Journal of Pharmacology and Experimental Therapeutics June 2001, 297 (3) 1137-1143;
Mizuho Tanabe
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Ichiro Ieiri
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Naoki Nagata
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Kazuko Inoue
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Soichiro Ito
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Yasunobu Kanamori
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Masakuni Takahashi
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Yasuo Kurata
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Junzo Kigawa
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Shun Higuchi
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Naoki Terakawa
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Kenji Otsubo
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Abstract

To evaluate whether mutations in the human multidrug resistance (MDR)-1 gene correlate with placental P-glycoprotein (PGP) expression, we sequenced the MDR-1 cDNA and measured PGP expression by Western blotting in 100 placentas obtained from Japanese women. Nine single nucleotide polymorphisms (SNPs) were observed with an allelic frequency of 0.005 to 0.420. Of these SNPs, G2677A (allelic frequency = 0.18) and G2677T (0.39) in exon 21 were associated with an amino acid conversion from Ala to Thr and to Ser, respectively. Sixty-one of 65 samples (93.8%), which had a C3435T allele, also had a mutant G2677(A,T) allele, suggesting an association between the two SNPs. Correlations of mutations with expression levels were observed; individuals having the G2677(A,T) and/or T-129C (p< 0.05) allele had less placental PGP. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based genotyping tests were developed for the detection of these SNPs. The PCR, in which genomic DNAs obtained from healthy subjects (n = 48) are used as samples, was successful. The frequency of mutations in placental cDNA was identical with that in genomic DNA. When genotype results were compared between Caucasians and Japanese, ethnic differences in the frequency of polymorphism in the MDR-1 gene were suspected. Although it remains to be determined whether these SNPs influence the pharmacokinetic and dynamic properties of clinically useful drugs that are substrates of PGP, the polymorphism of the MDR-1 gene presented here may provide useful information in in vivo study of these issues.

Footnotes

  • Send reprint requests to: Ichiro Ieiri, Ph.D., Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Nishi-machi 36-1, Yonago, 683-8504, Japan. E-mail:ieiri-ttr{at}umin.ac.jp

  • This study was supported by a grant from the Ministry of Education, Science, Sports, and Culture of Japan.

  • Abbreviations:
    PGP
    P-glycoprotein
    MDR-1
    multidrug resistance-1
    SNP
    single nucleotide polymorphism
    SSCP
    single-strand conformation polymorphism
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    PCR-RFLP
    PCR-restriction fragment length polymorphism
    TPBS
    1× phosphate-buffered saline, 0.1% Tween 20
    bp
    base pair(s)
    • Received December 27, 2000.
    • Accepted February 20, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 3
1 Jun 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Expression of P-glycoprotein in Human Placenta: Relation to Genetic Polymorphism of the Multidrug Resistance (MDR)-1 Gene

Mizuho Tanabe, Ichiro Ieiri, Naoki Nagata, Kazuko Inoue, Soichiro Ito, Yasunobu Kanamori, Masakuni Takahashi, Yasuo Kurata, Junzo Kigawa, Shun Higuchi, Naoki Terakawa and Kenji Otsubo
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1137-1143;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Expression of P-glycoprotein in Human Placenta: Relation to Genetic Polymorphism of the Multidrug Resistance (MDR)-1 Gene

Mizuho Tanabe, Ichiro Ieiri, Naoki Nagata, Kazuko Inoue, Soichiro Ito, Yasunobu Kanamori, Masakuni Takahashi, Yasuo Kurata, Junzo Kigawa, Shun Higuchi, Naoki Terakawa and Kenji Otsubo
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1137-1143;
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