Petrovic Vanja, Kojovic Dea, Cressman Alex, Piquette-Miller Micheline
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Int Immunopharmacol. 2015 Jun;26(2):349-56. doi: 10.1016/j.intimp.2015.04.020. Epub 2015 Apr 21.
Several efflux and uptake transporters in the placenta are involved in the transmembrane transport of endogenous substrates and xenobiotics. Their expression and function may be altered in maternal complications associated with inflammation. Our objective was to examine the effect of chorioamnionitis, a bacterial intra-amniotic infection on the expression of clinically important transporters in human placenta.
Human placental samples were collected from preterm and term pregnancies diagnosed with chorioamnionitis infection and were gestational age-matched with samples from pregnancies with no obstetric complications, using predefined exclusion criteria. Transporter protein expression was quantified using Western blots while cytokine and transporter mRNA expression was measured via real-time polymerase chain reaction.
mRNA levels of pro-inflammatory cytokines IL-6, IL-1β and TNF-α were markedly elevated by 2.5- to 3-fold in preterm placentas with infection, relative to preterm controls (p<0.05). Expression of ABCG2 and SLCO2B1 was downregulated by 48 to 57% (p<0.05) in placentas from women with infection and preterm parturition, relative to preterm healthy controls. Protein and mRNA expression changes were generally consistent. At term, ABCG2 mRNA and SLCO2B1 protein expression levels were significantly downregulated, relative to controls. Significant changes in ABCB1 and SLCO4A1 expression were not observed, however ABCB1 transcript levels strongly correlated with IL-6, IL-1β and TNF-α expression (p<0.001), potentially suggesting involvement of cytokine-mediated regulation.
Collectively, these data show that maternal infections impact the expression of key drug transporters in placenta, suggesting that materno-fetal drug transport may be altered by changes in placental expression of ABC and OATP transporters.
胎盘中的几种外排和摄取转运蛋白参与内源性底物和外源性物质的跨膜转运。它们的表达和功能可能在与炎症相关的母体并发症中发生改变。我们的目的是研究绒毛膜羊膜炎（一种羊膜腔内细菌感染）对人胎盘临床重要转运蛋白表达的影响。
使用预先定义的排除标准，从诊断为绒毛膜羊膜炎感染的早产和足月妊娠中收集人胎盘样本，并与无产科并发症妊娠的样本进行孕周匹配。使用蛋白质免疫印迹法定量转运蛋白的表达，同时通过实时聚合酶链反应测量细胞因子和转运蛋白的mRNA表达。
与早产对照组相比，感染的早产胎盘中促炎细胞因子IL-6、IL-1β和TNF-α的mRNA水平显著升高2.5至3倍（p<0.05）。与早产健康对照组相比，感染且早产的妇女胎盘中ABCG2和SLCO2B1的表达下调了48%至57%（p<0.05）。蛋白质和mRNA表达变化总体一致。足月时，相对于对照组，ABCG2 mRNA和SLCO2B1蛋白表达水平显著下调。未观察到ABCB1和SLCO4A1表达的显著变化，然而ABCB1转录水平与IL-6、IL-1β和TNF-α表达强烈相关（p<0.001），这可能表明细胞因子介导的调节参与其中。
总体而言，这些数据表明母体感染会影响胎盘中关键药物转运蛋白的表达，提示母胎药物转运可能会因ABC和OATP转运蛋白在胎盘表达的变化而改变。
