Placental drug transporters and their role in fetal protection.

ABSTRACT

The human placenta has a number of protective mechanisms that help to prevent potentially harmful compounds from entering the fetal compartment. Two important transporter proteins are phospho-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) which are mainly expressed in the syncytiotrophoblast where they actively extrude a wide range of xenobiotics. The expression profile of these transporters varies with advancing gestation. P-gp has been shown to decline near term, leaving the fetus susceptible to potentially teratogenic drugs commonly administered to pregnant women (i.e., synthetic glucocorticoids, selective serotonin reuptake inhibitors, glyburide, antiretrovirals, etc.). Drug transporter expression is regulated by a number of transcription factors, and steroid hormones present during pregnancy, such as progesterone, estrogen and corticosteroids. Drug transporter levels have also been found to be altered in pathological pregnancies (preterm, pre-eclampsia, growth restriction and infection). Genetic variation in the genes that encode these drug transporters can significantly alter transporter function and may play a significant role in determining the susceptibility of a fetus to maternally-administered therapeutic drugs. Understanding the regulation of placental drug transporters in normal and pathological pregnancies is critical to further our knowledge of fetal development, and may lead to the development of more selectively-targeted maternal and fetal drug treatments.