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1 Academic Unit of Child Health, University of Manchester, Manchester, United Kingdom
2 Paterson Institute of Cancer Research, Christie Hospital, Manchester, United Kingdom
* To whom correspondence should be addressed. E-mail: Diane.e.atkinson{at}man.ac.uk.
Natural differences in expression and retroviral transduction techniques were used to test the hypothesis that MDR1 P-glycoprotein (P-gp) and MRP1 (multidrug resistance related protein) contribute to xenobiotic handling by placental trophoblast. RT-PCR and Western blotting in placenta, primary cytotrophoblast cell cultures and in BeWo, JAr and JEG choriocarcinoma cell lines showed that MRP1 was ubiquitously expressed whilst MDR1 was absent or minimally expressed in BeWo and JEG cell lines. In syncytiotrophoblast, P-gp was localized predominantly to the microvillous, maternal facing, plasma membrane and MRP1 to the basal, fetal facing, plasma membrane. Functional studies showed that cyclosporin A sensitive accumulation of 3H-vinblastine by cells containing both transport proteins was significantly different from those expressing predominantly MRP1. Retroviral gene transfer of MDR1 to BeWo cells confirmed that this difference was due to the relative expression of MDR1. Therefore both P-gp and MRP1 contribute to xenobiotic handling by the trophoblast. Localization of P-gp to the microvillous membrane suggests an essential role in preventing xenobiotic accumulation by the syncytiotrophoblast and therefore in protecting the fetus.
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