The Role of Placental Breast Cancer Resistance Protein in the Efflux of Glyburide across the Human Placenta
Introduction
Recent research, using the ex vivo human placental perfusion model, has revealed that the sulfonylurea oral hypoglycemic agent, glyburide, is effluxed by an active mechanism against a concentration gradient from the fetal to the maternal compartment and that this mechanism is not affected by the P-glycoprotein inhibitor verapamil [1]. Of the human ABC transporters classified thus far, MRP1–3, BCRP (ABCG2), and P-glycoprotein have all been shown to play a role in protecting tissue from xenobiotic accumulation by actively extruding drugs from the cell [2]. Due to their high level of expression in the placenta, several of these ATP-binding cassette transporters have been implicated in the efflux of glyburide from the fetal to the maternal compartment. Of potential importance, BCRP/ABCG2, in particular, is highly expressed in the placental syncytiotrophoblast suggesting it may play a role in protecting the fetus from drug toxicity [3]. Further investigation, using glyburide uptake studies carried out on PgP, MRP1–3, and BCRP over expressing cell lines indicated that glyburide is preferentially transported by BCRP and MRP3 [4]. Additional research in our lab using placental brush border membrane vesicles revealed a significant increase in the vesicular uptake of glyburide in the presence of novobiocin, a BCRP inhibitor, while MRP3 inhibition did not demonstrate a similar effect [5]. There are limitations with using these in vitro systems in determining the overall contribution of a single transporter in vivo. The use of these methods in our lab were beneficial in allowing us to observe a single transporter's action in the absence of any other placental factors and narrow down which transporters may be responsible. However, there exists a need to further elucidate the contribution of BCRP in an ex vivo system where more contributing factors are present.
Several BCRP inhibitors have been identified to date. Specifically, the dihydropyridine, nicardipine, was shown to be a potent inhibitor of the intracellular accumulation of the BCRP substrate mitoxantrone using BCRP expressing human breast cancer MCF-7/MX100 cell lines [6], [7]. These studies determined that nicardipine was able to effectively reverse mitoxantrone resistance in HEK293 cells expressing BCRP at concentrations below 5 μM [6], [7]. The mechanism of interaction of nicardipine with BCRP has not been elucidated. However, based on investigations on interactions with PgP, it has been suggested that nicardipine interacts directly with BCRP or by modulation of BCRP ATPase activity [6]. The present study aimed at elucidating the potential role of BCRP in the active efflux of glyburide across the placental barrier using the dual perfusion system of isolated human placental lobules.
Section snippets
In vitro perfusion of human placental cotyledon
The study design has been approved by the ethics committee at the Hospital for Sick Children and Mount Sinai Hospital. Placentae were obtained with informed consent following elective cesarean section delivery of non-complicated term pregnancies. The placentae were transported to the lab in heparanized ice-cold phosphate-buffered saline (PBS). Placentae were examined for evidence of damage during delivery. Vein/artery pairs with minimal branching that supply the same intact lobule were chosen
Results
The mean mass (±SE) of the perfused cotyledons was 19.56 ± 6.3 (range 11.1–38.18). The fetal arterial pressures remained constant throughout the control and experimental periods. The rate of glucose and oxygen consumption did not vary between the experimental and control periods (Table 1). As well, the rate of lactate and hCG production showed little variance between the experimental and control periods (Table 1). The perfused cotyledons maintained the ability to utilize glucose and oxygen
Discussion
Results obtained from perfusions in the presence of the BCRP inhibitor show a significant increase in the mean fetal-to-maternal concentration ratio of glyburide determined at 180 min when compared to the mean fetal-to-maternal ratio obtained in the absence of inhibitor. Results indicate that nicardipine was able to partially block the transfer of glyburide across the placenta thorough inhibition of BCRP.
BCRP is a recently discovered transporter belonging to the ATP-binding cassette family of
Acknowledgements
GK and EP are supported by a grant from CIHR. GK is holder of the Research Leadership in better Pharmacotherapy during Pregnancy and Lactation at the Hospital for Sick Children and the Ivey Chair in Molecular Toxicology at the University of Western Ontario.
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