Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms.
The ABC transporter P-glycoprotein is a product of the MDR1 gene and its function in human placenta is to extrude xenobiotics from the tissue thus decreasing fetal exposure. The goal of this investigation was to examine the effect of three polymorphisms in the MDR1 gene on the expression and activity of placental P-gp. In 199 term placentas examined, the C1236T variant was associated with 11% lower P-gp protein expression than wild-type, while the C3435T and G2677T/A variants each were associated with a 16% reduction (p<0.05). Homozygotes for the C1236T and C3435T variant allele (TT) were associated with 42% and 47% increase in placental P-gp transport activity, respectively (p=0.04 and p=0.02) of the prototypic substrate, [(3)H]-paclitaxel. These findings indicate that the C3435T and G2677T/A SNPs in MDR1 are significantly associated with decreased placental P-gp protein expression, while the C1236T and C3245T homozygous variants are significantly associated with an increase in its efflux activity.
Hemauer
Sarah J
SJ
Department of Obstetrics & Gynecology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0587, USA. sjhemaue@utmb.edu
Nanovskaya
Tatiana N
TN
Abdel-Rahman
Sherif Z
SZ
Patrikeeva
Svetlana L
SL
Hankins
Gary D V
GD
Ahmed
Mahmoud S
MS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D001692:Biological Transport; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011247:Pregnancy
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1