Detailed understanding of the mechanisms employed in transfer of drugs across the placenta is essential for optimization of pharmacotherapy during pregnancy. Disclosure of drug efflux transporters as an "active component" of the placental barrier has brought new important insights into the field of transplacental pharmacokinetics. P-glycoprotein (P-gp, MDR1) is the first discovered and so far the best characterized of drug efflux transporters, whose role in the regulation of drug disposition to the fetus has been extensively studied. Expression of P-gp in the placental trophoblast layer was confirmed at the mRNA and protein levels in all phases of pregnancy, and several in vitro and in vivo studies demonstrated functional activity of the transporter in materno-fetal drug transport. P-gp is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, providing thus protection to the fetus. This review summarizes the current knowledge on the expression, localization and function of P-gp in the placenta. In addition, we include the latest data concerning transcriptional regulation of placental P-gp expression and polymorphisms of the MDR1 gene. Clinical significance of placental P-gp and its future perspectives for pharmacotherapy during pregnancy are also discussed.

• MeSH
• financování organizované MeSH
• geny MDR MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• maternofetální výměna látek MeSH
• messenger RNA metabolismus   MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• placenta cytologie   metabolismus   MeSH
• těhotenství MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

1. Breast cancer resistance protein (BCRP, ABCG2) is a drug efflux transporter that is believed to affect the drug disposition of several drugs and xenobiotics. In the present study, we evaluated the localization and functional expression of BCRP in the human choriocarcinoma cell line BeWo, an in vitro model of the human trophoblast, and compared it with the expression of P-glycoprotein (MDR1, ABCB1) as the most widely studied placental transporter. In addition, the expression of BCRP at the mRNA level was compared with that of MDR1 in the human term placenta. 2. Western blotting analysis revealed high endogenous expression of BCRP protein in BeWo cells. Using indirect immunofluorescence microscopy, we found that the BCRP transporter appears to be localized predominantly at the apical plasma membrane. Functional studies showed a significant effect of the BCRP inhibitors GF120918 (5 micromol/L) and Ko143 (1 micromol/L) on mitoxantrone accumulation and, thus, confirmed efflux activity of BCRP in BeWo cells. 3. Using absolute mRNA quantification with real-time reverse transcription-polymerase chain reaction, we found high expression of BCRP in BeWo cells, whereas no transcript of MDR1 (P-glycoprotein), the most extensively studied drug transporter, was detected. 4. In the human placenta, BCRP was localized predominantly in the syncytiotrophoblast layer; however, immunopositivity for the BXP-21 antibody was also observed in fetal vessels of the chorionic villi. The number of BCRP transcripts in the human term placenta was found to be more than 10-fold higher compared with the expression of MDR1. 5. In conclusion, we suggest that BeWo cells could serve as a suitable in vitro model to study trans-trophoblast transport of BCRP substrates and that placental BCRP can play an important role in preventing the accumulation of potentially toxic xenobiotics in the trophoblast cells.

• MeSH
• ABC transportéry antagonisté a inhibitory   genetika   metabolismus   MeSH
• akridiny farmakologie   MeSH
• biologický transport účinky léků   MeSH
• buněčná membrána metabolismus   MeSH
• buněčné linie MeSH
• choriokarcinom genetika   metabolismus   patologie   MeSH
• financování organizované MeSH
• fluorescenční mikroskopie MeSH
• imunohistochemie MeSH
• indoly farmakologie   chemie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mitoxantron farmakokinetika   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• placenta metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• regulace genové exprese u nádorů MeSH
• těhotenství MeSH
• tetrahydroisochinoliny farmakologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH