Review
Role of transporters in placental transfer of drugs

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Abstract

Human placenta functions as an important transport organ that mediates the exchange of nutrients and metabolites between maternal and fetal circulations. This function is made possible because of the expression of a multitude of transport proteins in the placental syncytiotrophoblast with differential localization in the maternal-facing brush border membrane versus the fetal-facing basal membrane. Even though the physiological role of most of these transport proteins is to handle nutrients, many of them interact with xenobiotics and pharmacological agents. These transport proteins therefore play a critical role in the disposition of drugs across the maternal–fetal interface, with some transporters facilitating the entry of drugs from maternal circulation into fetal circulation whereas others preventing such entry by actively eliminating drugs from the placenta back into maternal circulation. The net result as to whether the placenta enhances the exposure of the developing fetus to drugs and xenobiotics or functions as a barrier to protect the fetus from such agents depends on the types of transporters expressed in the brush border membrane and basal membrane of the syncytiotrophoblast and on the functional mode of these transporters (influx versus efflux).

Introduction

Placenta serves as the sole link between the mother and her developing fetus all through pregnancy. It plays an obligatory role in the growth and development of the fetus by performing a multitude of functions. It serves as an endocrine organ by producing various steroid hormones (e.g., estrogens and progesterone) and polypeptide hormones (e.g., chorionic gonadotropin and placental lactogen) relevant to pregnancy. It functions as a nutritive organ by mediating the transfer of essential nutrients such as glucose, amino acids, fatty acids, minerals, and vitamins from mother to fetus. It is also responsible for the exchange of oxygen and carbon dioxide between the maternal and fetal circulations. In addition, it plays a critical role in the elimination of various metabolic waste products such as bilirubin from the fetus. In order to perform many of these functions, placenta expresses numerous transporters. In a manner similar to intestine and kidney, placenta is capable of vectorial transfer of nutrients and metabolic waste products. Thus, placenta can mediate the transfer of certain compounds from mother to fetus and certain other compounds from fetus to mother. This is made possible by the polarized nature of syncytiotrophoblast, the functional unit of the placenta. Placental syncytiotrophoblast is a multinucleated cell that is formed by the fusion of differentiating cytotrophoblasts. The plasma membrane of syncytiotrophoblast consists of two distinct regions: a brush border membrane that is facing the maternal side and a basal membrane that is facing the fetal side. On the maternal side, there is no capillary network between the uterine arterioles and uterine venules because the invasion of the placental tissue into the uterine endometrium destroys the uterine blood vessels at the site of implantation. As a result, blood flows into the placental intervillous space and comes in direct contact with the brush border membrane of the syncytiotrophoblast without the intervening endothelium of the capillaries. In contrast, the umbilical vessels form a capillary network on the fetal side. The transfer of any compound from the maternal blood into fetal blood across the syncytiotrophoblast has to involve transport across the brush border membrane followed by transport across the basal membrane. Similarly, the transfer of any compound from the fetal blood into maternal blood has to involve transport across the basal membrane followed by transport across the brush border membrane. To facilitate this process, the two membranes express various transporters in a differential manner. The fetal capillary endothelium forms an additional barrier for the maternal–fetal exchange of nutrients and metabolites and, accordingly, this cell also expresses a wide variety of transporters to accomplish the exchange process.

Section snippets

Placental transporters as “drug transporters”

Placenta expresses specific transporters to serve specific physiological functions. A variety of endogenous compounds, which may be nutrients or metabolic waste products, are recognized as substrates by the placental transporters in a differential manner. The polarized distribution of transporters in the placental brush border membrane versus basal membrane enables placenta to facilitate the transfer of nutrients from mother to fetus and export of metabolic waste products from fetus to mother.

Monoamine transporters

Two different monoamine transporters are expressed in the placental brush border membrane (Balkovetz et al., 1989, Ramamoorthy et al., 1992, Ramamoorthy et al., 1993; for a review, see Ganapathy and Leibach, 1995, Ganapathy et al., 1999). The physiological substrates for these transporters are serotonin, dopamine, norepinephrine, and epinephrine. Serotonin transporter is specific for serotonin and is energized by transmembrane gradients for Na+, Cl, and K+. Since serotonin is a potent

Extraneuronal monoamine transporter

Placenta also expresses another monoamine transporter which transports serotonin, norepinephrine, and dopamine with low affinity (Grundemann et al., 1998, Kekuda et al., 1998, Wu et al., 1998a). The transport function is not dependent on Na+ but is influenced by membrane potential. This transporter is called extraneuronal monoamine transporter to differentiate it from the neuronal monoamine transporters (i.e., serotonin transporter, norepinephrine transporter, and dopamine transporter). It is

Organic cation transporter OCTN1

OCTN1 (a novel organic cation transporter) is structurally related to OCT3 and both transporters belong to the same gene family (SLC22) (Tamai et al., 1997). However, there are significant differences between OCTN1 and OCTs in terms of transport mechanism and therefore OCTN1 is designated as a distinct subfamily within SLC22 (Koepsell and Endou, 2004). It is expressed at high levels in placenta (Wu et al., 2000). The physiological function of this transporter is not clear because little is

Carnitine transporter (OCTN2)

OCTN2 is structurally very similar to OCTN1 (Wu et al., 1998b). It functions as a Na+-coupled transporter for carnitine (Tamai et al., 1998). Several studies have shown that the placental brush border membrane possesses an active Na+-coupled mechanism for the transport of carnitine (Lahjouji et al., 2004, Roque et al., 1996). Recent evidence indicates that OCTN2 is expressed in this membrane (Lahjouji et al., 2004). The physiological function of this transporter is to mediate active transfer of

Reduced folate transporter

Folate is an essential nutrient for the developing fetus. It is transferred across the placenta by a concerted action of a folate receptor in the brush border membrane and the reduced folate transporter in the basal membrane (Ganapathy et al., 2004). The predominant form of folate in circulation is N5-methyltetrahydrofolate. Folate receptor is a protein anchored to the placental brush border membrane by a lipid anchor and it mediates the entry of folate into placenta by receptor-mediated

Monocarboxylate transporters (MCTs)

There are several isoforms of monocarboxylate transporters (MCTs) (Halestrap and Meredith, 2004) and placenta expresses many of them. Even though it is known that the transport function attributable to MCTs is present in the brush border membrane (Balkovetz et al., 1988) as well as in the basal membrane (Inuyama et al., 2002), the molecular identity of the transporter isoform responsible for the transport function has not yet been established. Under physiological conditions, the primary

Equilibrative nucleoside transporters (ENT1 and ENT2)

Equilibrative nucleoside transporters (ENTs) are bidirectional and Na+-independent transporters for purine and pyrimidine nucleosides. The brush border membranes as well as basal membranes from placenta possess nucleoside transport activity (Barros et al., 1991). Two different types of equilibrative nucleoside transporters have been cloned from placenta. One is ENT1 which is also known as es (equilibrative nucleoside transporter that is sensitive to inhibition by nitrobenzylthioinosine) (

Multidrug resistance protein (MDR1) and breast cancer resistance protein (BCRP)

Multidrug resistance protein MDR1 and the breast cancer resistance protein BCRP (also known as placenta-specific ABC transporter) are widely regarded as drug transporters because much is known about their role in drug transport. However, these transporters do have physiological functions. MDR1 is likely to play a role in cholesterol distribution in the membrane (Garrigues et al., 2002) and BCRP may function in the homeostasis of porphyrins (Jonker et al., 2002). Both transporters are located in

Anion transporters

Placenta plays an important role in steroid hormone metabolism. One of the modifications of steroid hormones during metabolism is sulfation. Steroid sulfates are transported from the placenta across the brush border membrane as well as the basal membrane. Transport systems are needed to facilitate this transfer process. There are several anion transporters expressed in both membranes of the syncytiotrophoblast. Organic anion transporting polypeptide-B (SLC21A9) and organic anion transporter-4

Conclusions

Placenta is an active transport organ. It expresses a multitude of transporters to carry out this transport function. It is capable of vectorial transport, transporting substrates from mother to fetus as well as from fetus to mother. The vectorial transport is made possible by differential expression of different transporters in the maternal-facing brush border membrane and fetal-facing basal membrane. The primary role of placental transporters is to provide nutrients to the developing fetus

Acknowledgment

This work is supported by the National Institutes of Health grant HD44404.

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