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1 Liggins Institute, University of Auckland, Auckland, New Zealand
2 Department of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand
3 Liggins Institute, University of Auckland, Auckland, New Zealand; Department of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand
* To whom correspondence should be addressed. E-mail: d.evseenko{at}auckland.ac.nz.
Introduction. ABC efflux transporters are expressed in the human placenta where they are thought to help protect the fetus from xenobiotics. To evaluate models for analysis of ABC transporter function and regulation in the placenta we have characterized the expression and activity of multi drug resistance 1/P glycoprotein (MDR1/Pgp), MDR3/Pgp, breast cancer resistance protein (BCRP), and multidrug resistance proteins 1 and 2 (MRPs 1, 2) in differentiating primary trophoblast cells and BeWo and Jar cell lines. Materials and methods. Real-time PCR and immunoblotting were used for analysis of mRNA and protein expression, respectively. Functional activity was measured using selective inhibitors of efflux of fluorescent substrates, calcein AM (Pgp and MRPs) and Hoechst 33342 (BCRP). Results. The levels of MDR1 mRNA and protein expression were much higher in trophoblast than in Jar and especially BeWo cells. Expression of MDR3 protein was also lower in BeWo cells. Levels of MDR3 expression were markedly higher then MDR1 levels in all tested cell types. Levels of both MDR1 and MDR3 expression decreased during trophoblast differentiation/syncytialization. BCRP was highly expressed in all cell types and increased with trophoblast differentiation. MRP1 expression was much lower in trophoblasts compared to both cell lines. In contrast to its abundant mRNA expression, MRP2 protein was practically undetectable in BeWo and Jar cells and was present only at very low levels in trophoblast. Functional studies confirmed presence of active Pgp and BCRP in all studied cell types, while MRP functional activity was detected only in BeWo and Jar cells. Summary and conclusions. Both cell lines may be useful models for studying various aspects of placental ABC transporter expression and function, but also have significant limitations. With respect to their ABC protein expression profile, Jar cells are more similar to non-differentiated cytotrophoblast, while BeWo appear to more closely reflect differentiated syncytiotrophoblast.
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