MRP isoforms and BCRP mediate sulfate conjugate efflux out of BeWo cells

Abstract

The breast cancer resistance protein (BCRP) and the multidrug resistance-associated proteins (MRPs) have the ability to eliminate sulfate conjugates but it is not known if this constitutes one of their roles in the placenta. To determine this, the BeWo cell line was used as a model of placental trophoblast cells and we examined the mechanisms of elimination of two common sulfotransferase substrates, 4-nitrophenol and acetaminophen. At 0.5-200 μM, neither 4-nitrophenyl sulfate nor acetaminophen sulfate affected the accumulation of the BCRP substrates BODIPY FL prazosin or mitoxantrone in BeWo monolayers, indicating a lack of interaction of BCRP with the sulfates. Efflux studies and bidirectional transport studies examining the effect of BCRP/MRP inhibitors on the efflux of intracellularly generated 4-nitrophenyl sulfate and acetaminophen sulfate, indicated that one or more of the MRP isoforms play a major role in the elimination of 4-nitrophenyl sulfate and acetaminophen sulfate across the basolateral (fetal-facing) and apical (maternal-facing) membranes respectively. BCRP played a minor role in the elimination of these two sulfate conjugates across the apical membrane. Our study shows that a yet undetermined role of trophoblast efflux transporters is the elimination of sulfate conjugates.

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

“…In studies with the BeWo cells, the model substrates 4-nitrophenyl sulfate and acetaminophen sulfate displayed minimal interaction with BCRP. However, the studies indicated that one or more of the MRP isoforms namely MRP1 and/or 5 but not limited to these, play a major role in the elimination of acetaminophen sulfate across the apical side (maternal facing) and 4-nitrophenyl sulfate across the basolateral side (fetal facing) of the trophoblast cells (155). Biondi et al showed that the MRP1 was responsible for the efflux of c-AMP from the forskolin and prostaglandin E2 (PGE2) stimulated trophoblast cells.…”

Efflux transport of chrysin and apigenin sulfates in HEK293 cells overexpressing SULT1A3: The role of multidrug resistance-associated protein 4 (MRP4/ABCC4)

“…In vitro and animal studies have indicated that the efflux transporters breast cancer resistance protein (BCRP) and/or multidrug resistance-associated proteins (MRPs) are main contributors to excretion of sulfates [17][18][19][20][21][22][23][24]. Of note, there is a species difference in sulfate recognition by the transporters.…”

ATP-binding cassette proteins BCRP, MRP1 and P-gp expression and localization in the human umbilical cord

“…They have also been well characterized in primary placental cell cultures, the immortalized placental cell lines BeWo, Jar and JEG3 (Evseenko et al, 2006; Ikeda et al, 2012) and in cord blood derived cells, including hematopoietic progenitor, stromal and mesenchymal cells (Ahmed et al, 2008; Alt et al, 2009; Seo et al, 2011; Wagner-Souza et al, 2008; Zhang et al, 2007). In these tissues and cells BCRP, MRP1 and P-gp play roles in trans-placental transport of bilirubin and bile acids (Azzaroli et al, 2007; Cui et al, 2009; Pascolo et al, 2001), cytokines and steroid hormones (Evseenko et al, 2007; Wang et al, 2008; Yasuda et al, 2006) drugs used in pregnancy (Beghin et al, 2010; Feinshtein et al, 2010; Gedeon et al, 2008; Hemauer et al, 2010; Hodyl et al, 2013; Manceau et al, 2012; Mitra and Audus 2010; Pollex et al, 2010), and common environmental chemicals such as Bisphenol A, the heavy metal cadmium and the pesticide chlorpyrifos (Jin and Audus 2005; Kummu et al, 2012; Ridano et al, 2012). …”