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.