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VARIABLE EXPRESSION OF MRP2 (ABCC2) IN HUMAN PLACENTA: INFLUENCE OF GESTATIONAL AGE AND CELLULAR DIFFERENTIATION

Department of Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics (H.E.M., G.J., M.G., S.H., I.C., H.K.K.), and Department of Neonatology, Ernst-Moritz-Arndt-University, Greifswald, Germany (K.L., C.F.)

MRP2 (ABCC2) is an ATP-binding cassette (ABC)-type membrane protein involved in transport of conjugates of various drugs and endogenous compounds. MRP2 has been localized to the apical membrane of syncytiotrophoblasts and is assumed to be involved in diaplacental transfer of the above substances. It has been shown that both genetic and environmental factors can influence MRP2 expression. We therefore investigated whether gestational age, cellular differentiation, and genetic polymorphisms influence expression and localization of MRP2 in 58 human placenta samples. We detected a significant increase of transporter-mRNA with gestational age by quantitative real-time polymerase chain reaction (MRP2 mRNA/18S rRNA ratio x 1000 ± S.D.; 0.43 ± 0.13 in early preterms versus 1.18 ± 0.44 in late preterms versus 2.1 ± 0.63 in terms; p < 0.05). MRP2 protein followed the mRNA amount as shown by Western blotting (mean relative band intensity ± S.D.; 0.56 ± 0.1 versus 0.7 ± 0.18 versus 0.92 ± 0.19; early preterms versus terms p < 0.05). In cultured cytotrophoblasts, MRP2 expression increased with differentiation to syncytiotrophoblasts, with a peak on day 2 (MRP2 mRNA/18S rRNA ratio x 1000 ± S.D.; 0.06 ± 0.01 versus 0.88 ± 0.27 versus 0.24 ± 0.02 on days 0, 2, and 4). Moreover, we studied the effect of single nucleotide polymorphisms (C–24T; G1249A, and C3972T) in the MRP2 gene on placental expression. One of these polymorphisms (G1249A) resulted in a significantly reduced expression of MRP2 mRNA in preterms. In summary, the expression of MRP2 in human placenta is influenced by gestational age, cellular differentiation, and genetic factors.

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