ATP-Binding Cassette Transporter Expression in Human Placenta as a Function of Pregnancy Condition

Abstract

ABSTRACT:Fetal drug exposure is determined by the type and concentration of placental transporters, and their regulation is central to the development of new treatments and delivery strategies for pregnant women and their fetuses. We tested the expression of several clinically important transporters in the human placenta associated with various pregnancy conditions (i.e., labor, preeclampsia, and preterm labor-inflammation). Placentas were obtained from five groups of women at the time of primary cesarean section: 1) term no labor; 2) term labor; 3) preterm no labor (delivered for severe preeclampsia); 4) preterm labor without inflammation (PTLNI); and 5) preterm labor with inflammation (PTLI). Samples were analyzed by Western blot and immunohistochemistry to identify changes in protein expression. Relative mRNA expression was determined by quantitative real-time polymerase chain reaction. A functional genomic approach was used to identify placental gene expression and elucidate molecular events that underlie the given condition. Placental expression of ATP-binding cassette transporters from women in labor and women with preeclampsia was unaltered. Multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) and mRNA expression increased in placentas of women with preterm labor with inflammation. Molecular pathways of genes up-regulated in PTLI samples included cytokinecytokine receptor interactions and inflammatory response compared with those in the PTLNI group. The mRNA expression of MDR1 and BCRP was correlated with that of interleukin-8, which also increased significantly in PTLI samples. These data suggest that the transfer of drugs across the placenta may be altered in preterm pregnancy conditions associated with inflammation through changes in MDR1 and BCRP.

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

“…Despite decreased P-gp immunostaining in the syncytiotrophoblast, we observed increased ABCB1 mRNA expression. This latter result is consistent with a previous study demonstrating that chorioamnionitis increased ABCB1 mRNA in the human placenta [51]. This disconnect between mRNA and protein has been previously described [49, 52], and may indicate post-transcriptional influences of inflammation.…”

Associations Between ABCG2 Gene Polymorphisms and Isolated Septal Defects in a Han Chinese Population

“…The fetal placenta consists of syncytiotrophoblast and cytotrophoblast layers. The BCRP is located in the maternalfacing apical membrane of the syncytiotrophoblast and the fetal blood vessels of the villous core, both of which are of fetal origin (Weier et al, 2008;Prouillac and Lecoeur, 2010;Mason et al, 2011;Ni and Mao, 2011;Iqbal et al, 2012;Staud et al, 2012). Therefore, only the genotypes of 421C > A and 34G > A polymorphisms in the ABCG2 gene of the children (but not mothers) might be associated with altered BCRP expression and transport activity in placenta, thereby modifying the inter-individual susceptibility to CHDs.…”

Effect of Prostaglandin E2on Multidrug Resistance Transporters In Human Placental Cells

“…In other examples of chronic inflammation, such as that observed in subjects with rheumatoid arthritis, Pgp expression is increased (Dumoulin et al, 1997;Llorente et al, 2000). We previously documented up-regulation of placenta Pgp and BCRP expression in the presence of histologic chorioamnionitis (Mason et al, 2011). Taken together, the findings suggest there are many interactive and reactive mediators of inflammation that can alter these transporters in the placenta.…”

“…Many drugs commonly administered to pregnant women such as glyburide (Zhou et al, 2008), nitrofurantoin , and cimetidine (Pavek et al, 2005) are BCRP substrates, and its induction may affect how these drugs are distributed and cleared during pregnancy. The importance of BCRP in placenta is further recognized by its presence on the fetal blood vessel endothelial cells Yeboah et al, 2006;Mason et al, 2011), where it could efflux potentially harmful exogenous and endogenous substrates into the fetal circulation. In this case, up-regulation of BCRP in fetal blood vessel endothelial cells could have an impact on transport toward the fetus.…”

“…Primer sequences for both Pgp and BCRP amplifications were previously described (Mason et al, 2011). 18s rRNA was used to normalize mRNA expression levels.…”