Biol. Pharm. Bull. 27(6) 753—759 (2004)

The placenta forms a selective barrier that functions to transport nutrients and fetal wastes in the appropriate directions. Syncytiotrophoblasts, which form the surface of the placental villi, play an essential role in restricting drug import through the blood-placenta barrier (BPB) to the fetus (Chart 1). The apical surface of the syncytiotrophoblast layer is the maternal-facing membrane, and makes direct contact with the maternal environment, while the basal side of the syncytiotrophoblast layer faces the fetal environment. Nutrient and waste transport across the syncytiotrophoblast layer is thought to be regulated by the polarized expression of transporters in the apical or basal membrane. Indeed, polarized expression of transporters, such as P-glycoprotein (Pgp), multidrug resistance protein 2 (MRP2) and L-type amino acid transporter-1 (LAT1), has been reported at the plasma membranes on the maternal blood side in syncytiotrophoblast cells, and divalent metal transporter-1 (DMT1), organic anion transporting polypeptide-B (OATP-B), and MRP1 are expressed at plasma membranes on the fetal blood side of syncytiotrophoblast cells. It is anticipated that drugs in the maternal circulation will preferentially inhibit the transporters expressed on the apical membrane of syncytiotrophoblast layers compared with those of the basal membrane, and vice versa. Pregnancy is a dynamic state, and drugs have potential use for curing disorders of the mother or the fetus. According to surveys of drug use during pregnancy, fetuses are exposed to prescription and non-prescription drugs prenatally or perinatally. Therefore, analysis of the placental transport of drugs, nutrients, and fetal wastes is important in connection with normal fetal development and pregnancy. In the BPB, many transporters play important roles during the development of the fetus and the fetal brain. Syncytiotrophoblasts express many nutrient transporters and regulate the transplacental movement of glucose, amino acids, fatty acids, and nucleosides. However, the regulatory mechanisms governing the polarized expression of the transporters, and the interactions between the transporters and drugs are still poorly understood. In vitro experiments using freshly isolated cells, primary cultured cells, and immortalized cell lines are very useful tools for elucidating those transporter functions, as well as the physiological and biological functions of the BPB. Immortalized cell lines are especially useful for the study of BPB functions, because it is difficult to collect large amounts of primary syncytiotrophoblast cells. In fact, human chorionic carcinoma cell lines, such as BeWo and JAR cells, have been mainly used for analysis of transporter activities and hormone secretion in the placenta (Table 1). However, it is difficult to extrapolate evidence obtained using these conventional cell lines to the in vivo situation. For example, results obtained with these conventional cell lines cannot be extrapolated to the second trimester. In addition, these cell lines lack the ability to incorporate endogenous substrates, such as dehydroepiandrosterone-3-sulfate (DHEA-S). Since immortalized cell lines from animals can allow us to analyze the relationship between in vitro and in vivo results, they are useful tools for the study of the BPB. However, the rodent placenta has not been used to study BPB functions, because the placental structures of human and rodent are different (Charts 1, 2). In the human placenta, cytotrophoblasts and syncytiotrophoblasts are found in villous and extravillous locations. Human syncytiotrophoblasts are not only capable of functioning as a transport barrier, they are also responsible for hormone production. In rats, the chorioallantoic placenta helps regulate the development of the fetus as gestation progresses. The morphology of the chorioallantoic placenta changes, and the placenta divides into functionally distinct junctional and labyrinth zones. The junctional zone is located at the maternal interface, while the June 2004 Biol. Pharm. Bull. 27(6) 753—759 (2004) 753