RT Journal Article
SR Electronic
T1 Expression of P-glycoprotein in Human Placenta: Relation to Genetic Polymorphism of the Multidrug Resistance (MDR)-1 Gene
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1137
OP 1143
VO 297
IS 3
A1 Mizuho Tanabe
A1 Ichiro Ieiri
A1 Naoki Nagata
A1 Kazuko Inoue
A1 Soichiro Ito
A1 Yasunobu Kanamori
A1 Masakuni Takahashi
A1 Yasuo Kurata
A1 Junzo Kigawa
A1 Shun Higuchi
A1 Naoki Terakawa
A1 Kenji Otsubo
YR 2001
UL http://jpet.aspetjournals.org/content/297/3/1137.abstract
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. The American Society for Pharmacology and Experimental Therapeutics