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, Kenji Otsubo

Research output: Contribution to journalArticle

497 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1137-1143
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume297
Issue number3
Publication statusPublished - Jun 1 2001
Externally publishedYes

Fingerprint

MDR Genes
P-Glycoprotein
Genetic Polymorphisms
Placenta
Single Nucleotide Polymorphism
Alleles
Complementary DNA
Polymerase Chain Reaction
Mutation
DNA
Multiple Drug Resistance
Mutation Rate
Restriction Fragment Length Polymorphisms
Exons
Healthy Volunteers
Pharmacokinetics
Western Blotting
Genotype
Amino Acids
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Expression of P-glycoprotein in human placenta : Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. / Tanabe, Mizuho; Ieiri, Ichiro; Nagata, Naoki; Inoue, Kazuko; Ito, Soichiro; Kanamori, Yasunobu; Takahashi, Masakuni; Kurata, Yasuo; Kigawa, Junzo; Higuchi, Shun; Terakawa, Naoki; Otsubo, Kenji.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 297, No. 3, 01.06.2001, p. 1137-1143.

Research output: Contribution to journalArticle

Tanabe, M, Ieiri, I, Nagata, N, Inoue, K, Ito, S, Kanamori, Y, Takahashi, M, Kurata, Y, Kigawa, J, Higuchi, S, Terakawa, N & Otsubo, K 2001, 'Expression of P-glycoprotein in human placenta: Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene', Journal of Pharmacology and Experimental Therapeutics, vol. 297, no. 3, pp. 1137-1143.
Tanabe, Mizuho ; Ieiri, Ichiro ; Nagata, Naoki ; Inoue, Kazuko ; Ito, Soichiro ; Kanamori, Yasunobu ; Takahashi, Masakuni ; Kurata, Yasuo ; Kigawa, Junzo ; Higuchi, Shun ; Terakawa, Naoki ; Otsubo, Kenji. / Expression of P-glycoprotein in human placenta : Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 297, No. 3. pp. 1137-1143.
@article{a60c40c07eeb435ca5f7698129ccb16d,
title = "Expression of P-glycoprotein in human placenta: Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene",
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.",
author = "Mizuho Tanabe and Ichiro Ieiri and Naoki Nagata and Kazuko Inoue and Soichiro Ito and Yasunobu Kanamori and Masakuni Takahashi and Yasuo Kurata and Junzo Kigawa and Shun Higuchi and Naoki Terakawa and Kenji Otsubo",
year = "2001",
month = "6",
day = "1",
language = "English",
volume = "297",
pages = "1137--1143",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Expression of P-glycoprotein in human placenta

T2 - Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene

AU - Tanabe, Mizuho

AU - Ieiri, Ichiro

AU - Nagata, Naoki

AU - Inoue, Kazuko

AU - Ito, Soichiro

AU - Kanamori, Yasunobu

AU - Takahashi, Masakuni

AU - Kurata, Yasuo

AU - Kigawa, Junzo

AU - Higuchi, Shun

AU - Terakawa, Naoki

AU - Otsubo, Kenji

PY - 2001/6/1

Y1 - 2001/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0034997034&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034997034&partnerID=8YFLogxK

M3 - Article

VL - 297

SP - 1137

EP - 1143

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -