Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.
Toxicol Appl Pharmacol. 2014 May 15;277(1):77-85. doi: 10.1016/j.taap.2014.02.019. Epub 2014 Mar 11.
Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis.
对乙酰氨基酚被用作孕妇缓解疼痛的首选药物。在这里，我们研究了亚毒性剂量的对乙酰氨基酚对母性胆汁淤积时滋养细胞 ABC 外排泵表达的影响及其对胎盘屏障的功能影响。用对乙酰氨基酚孵育人绒毛癌细胞（JAr、JEG-3 和 BeWo）48h 不会导致 MDR1 和 MRPs 的表达和/或活性发生显著变化。相比之下，在 JEG-3 细胞中，BCRP mRNA、蛋白和转运活性降低。在妊娠末期收集的大鼠胎盘，给予对乙酰氨基酚 3 天的最后一天，导致 Mrp1 和 Bcrp 的 mRNA 水平增强，但蛋白水平不变。事实上，发现 Bcrp 蛋白减少。使用原位灌注大鼠胎盘，发现用对乙酰氨基酚处理母鼠后，Bcrp 依赖性胎儿向母体胆汁酸转运减少。在妊娠大鼠中完全胆道阻塞导致胎儿血清和组织中胆汁酸蓄积增加，当母亲用对乙酰氨基酚治疗时，这种蓄积进一步增加。这种药物在 JEG-3 细胞中诱导 ROS 产生增加，并降低大鼠胎盘的总谷胱甘肽含量。此外，NRF2 途径在 JEG-3 细胞中被激活，表现为核 NRF2 水平增加和 NRF2 靶基因 NQO1 和 HMOX-1 的上调，而在大鼠胎盘未观察到。总之，对乙酰氨基酚在胎盘诱导氧化应激和 BCRP/Bcrp 下调，这可能会损害母性胆汁淤积时胎盘对胆汁酸的屏障功能。
