Expression of P-glycoprotein in human placenta: Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene

Citation
M. Tanabe et al., Expression of P-glycoprotein in human placenta: Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene, J PHARM EXP, 297(3), 2001, pp. 1137-1143
Citations number
24
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
297
Issue
3
Year of publication
2001
Pages
1137 - 1143
Database
ISI
SICI code
0022-3565(200106)297:3<1137:EOPIHP>2.0.ZU;2-4
Abstract
To evaluate whether mutations in the human multidrug resistance (MDR)-1 gen e correlate with placental P-glycoprotein (PGP) expression, we sequenced th e MDR-1 cDNA and measured PGP expression by Western blotting in 100 placent as 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 (alielic frequency = 0.18) and G2677T (0.39) in exon 21 were associ ated 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 mu tant G2677(A,T) allele, suggesting an association between the two SNPs. Cor relations of mutations with expression levels were observed; individuals ha ving the G2677(A,T) and/or T-129C (p < 0.05) allele had less placental PGP. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RF LP)-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 cD NA was identical with that in genomic DNA. When genotype results were compa red between Caucasians and Japanese, ethnic differences in the frequency of polymorphism in the MDR-1 gene were suspected. Although it remains to be d etermined whether these SNPs influence the pharmacokinetic and dynamic prop erties of clinically useful drugs that are substrates of PGP, the polymorph ism of the MDR-1 gene presented here may provide useful information in in v ivo study of these issues.