Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1).
The MDR1 gene product P-glycoprotein in the human placenta is important for protecting the fetus from unintended, harmful drug exposure, but also for limiting the access of therapeutic drugs to the fetus after maternal drug intake. A polymorphism in exon 26 of the MDR1 gene (C3435T) has previously been shown to be associated with reduced P-glycoprotein expression in the small intestine, kidney and lymphocytes. In the present study, we examined systematically whether MDR1 polymorphisms also have an impact on P-glycoprotein expression in the human placenta. MDR1 mRNA and P-glycoprotein were analysed in 73 full-term human placentas of Caucasians, as well as respective MDR1 genotypes/haplotypes, for the C3435T and G2677T/A polymorphisms of mothers and infants. MDR1 mRNA levels were not different between these genotype groups. However, P-glycoprotein expression was significantly lower when both mother and infant were homozygous for the 3435T allele (TT/tt) compared to maternal and fetal homozygotes for the C-allele (0.40 +/- 0.18 a.u. for TT/tt versus 0.66 +/- 0.30 a.u. for CC/cc, P = 0.01). Moreover, placentas from mothers carrying both polymorphisms (3435T and 2677T; TT/TT) also had a significantly lower P-glycoprotein expression (0.31 +/- 0.12 a.u.) compared to placentas of wild-type individuals (CC/GG, 0.71 +/- 0.31 a.u., P = 0.02). Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus.
Hitzl
Monika
M
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Schaeffeler
Elke
E
Hocher
Berthold
B
Slowinski
Torsten
T
Halle
Horst
H
Eichelbaum
Michel
M
Kaufmann
Peter
P
Fritz
Peter
P
Fromm
Martin F
MF
Schwab
Matthias
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D010641:Phenotype; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers