Multidrug resistance-associated protein (MRP) isoforms and the breast cancer resistance protein (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 fate of two common sulfotransferase substrates, 4-nitrophenol and acetaminophen. At 0.5–200 μM, acetaminophen sulfate did not alter the accumulation of the BCRP substrates BODIPY FL prazosin or mitoxantrone in BeWo monolayers indicating a lack of interaction of BCRP with acetaminophen sulfate. 4-nitrophenyl sulfate increased the accumulation of BODIPY FL prazosin only at 200 μM, indicating it to be a BCRP inhibitor at high concentrations. 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 played a major role in the elimination of 4-nitrophenyl sulfate and acetaminophen sulfate across the basolateral (fetal-facing) and apical (maternal-facing) trophoblast membranes respectively. BCRP played only 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