Mathias Anita A, Hitti Jane, Unadkat Jashvant D
Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195, USA.
Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R963-9. doi: 10.1152/ajpregu.00173.2005. Epub 2005 Jun 16.
Placental efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) protect the developing fetus from exposure to potentially toxic xenobiotics. However, little is known about the expression of these transporters in human placentae of different gestational ages. Therefore, we quantified the expression of P-gp and BCRP in human placentae of different gestational ages. We also measured the expression of various nuclear regulatory factors such as the pregnane xenobiotic factor to determine whether their expression also changes with gestational age. Syncitial microvillous plasma membranes were isolated from human placentae of various gestational ages (60-90 days, 90-120 days, and full-term C-section placentae). P-gp and BCRP expression (protein) in these preparations were measured by Western blot analysis followed by an ELISA. Expression (mRNA) of P-gp, BCRP, and nuclear regulatory factors in the placentae were quantified by quantitative real-time PCR. P-gp expression (relative to that of alkaline phosphatase) was significantly (P < 0.05) higher (44.8-fold as protein; 6.5-fold as mRNA) in early gestational age human placentae (60-90 days) vs. term placentae. In contrast, BCRP (protein and mRNA) and nuclear regulatory factors (mRNA) expression in placental tissue did not change significantly with gestational age. However, placental expression of P-gp and human chorionic gonadotropin-beta (hCG-beta) transcripts was highly correlated (r = 0.73; P < 0.0001; Spearman rank correlation). Expression of P-gp, but not BCRP, decreases dramatically with gestational age in human placentae. This decrease in P-gp expression is not caused by a change in expression of nuclear receptor transcripts but appears to be related to hCG-beta expression. The placental P-gp expression appears to be upregulated in early pregnancy to protect the fetus from xenobiotic toxicity at a time when it is most vulnerable to such toxicity.
胎盘外排转运蛋白，如P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP），可保护发育中的胎儿免受潜在有毒外源性物质的影响。然而，关于这些转运蛋白在不同孕周人胎盘中的表达情况，人们了解甚少。因此，我们对不同孕周人胎盘中P-gp和BCRP的表达进行了定量分析。我们还检测了各种核调节因子的表达，如孕烷外源性因子，以确定它们的表达是否也随孕周而变化。从不同孕周（60 - 90天、90 - 120天以及足月剖宫产胎盘）的人胎盘中分离出合体微绒毛质膜。通过蛋白质印迹分析和酶联免疫吸附测定法检测这些制剂中P-gp和BCRP的表达（蛋白质）。通过定量实时聚合酶链反应对胎盘中P-gp、BCRP和核调节因子的表达（信使核糖核酸）进行定量分析。与足月胎盘相比，孕早期人胎盘（60 - 90天）中P-gp的表达（相对于碱性磷酸酶）显著升高（蛋白质水平升高44.8倍；信使核糖核酸水平升高6.5倍）（P < 0.05）。相比之下，胎盘组织中BCRP（蛋白质和信使核糖核酸）和核调节因子（信使核糖核酸）的表达并未随孕周发生显著变化。然而，胎盘P-gp和人绒毛膜促性腺激素β（hCG-β）转录本的表达高度相关（r = 0.73；P < 0.0001；Spearman等级相关）。在人胎盘中，P-gp而非BCRP的表达随孕周显著下降。P-gp表达的下降并非由核受体转录本表达的变化引起，而是似乎与hCG-β的表达有关。胎盘P-gp的表达在妊娠早期似乎上调，以便在胎儿最易受此类毒性影响时保护其免受外源性物质的毒性作用。
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