Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
Drug Metab Dispos. 2023 Oct;51(10):1308-1315. doi: 10.1124/dmd.122.001080. Epub 2023 Jun 7.
Recent studies have demonstrated downregulation of breast cancer resistance protein (BCRP/ABCG2) in placenta obtained from women with preeclampsia (PE). BCRP is highly expressed in placenta and plays an important role in preventing xenobiotics from entering the fetal compartment. Although PE is often therapeutically managed with drugs that are substrates of BCRP, there are limited studies on the impact of PE on fetal drug exposure. Due to ethical concerns, use of preclinical models is an important approach. Thus, by using proteomic and traditional methods, we characterized transporter changes in an immunologic rat model of PE to determine its utility and predictive value for future drug disposition studies. PE was induced by daily administration of low-dose endotoxin (0.01-0.04 mg/kg) to rats on gestational days (GD) 13-16, urine was collected, and rats were sacrificed on GD17 or GD18. PE rats shared similar phenotype to PE patients, including proteinuria, and increased levels of tumor necrosis factor and interleukin 6. Transcript and protein levels of Bcrp were significantly downregulated in placenta of PE rats on GD18. multidrug resistance 1a, multidrug resistance 1b, and organic anion transporting polypeptide 2B1 mRNA were also decreased in PE. Proteomics revealed activation of various hallmarks of PE including immune activation, oxidative stress, endoplasmic reticulum stress and apoptosis. Overall, our results demonstrated that the immunologic PE rat model exhibits numerous similarities to human PE along with dysregulation of placental transporters. Therefore, this model may be useful in examining the impact of PE on the maternal and fetal disposition of BCRP substrates. SIGNIFICANCE STATEMENT: Fully characterizing preclinical models of disease is necessary to determine their validity to human conditions. Combining traditional and proteomic methods of model characterization, we identified numerous phenotypic similarities between our model of preeclampsia and human disease. The alignment with human pathophysiological changes allows for more confident use of this preclinical model.
最近的研究表明，子痫前期（PE）患者胎盘的乳腺癌耐药蛋白（BCRP/ABCG2）表达下调。BCRP 在胎盘组织中高度表达，在防止外源性物质进入胎儿隔室方面发挥着重要作用。虽然 PE 通常通过 BCRP 底物的药物进行治疗，但关于 PE 对胎儿药物暴露的影响的研究有限。由于伦理问题，使用临床前模型是一种重要的方法。因此，我们使用蛋白质组学和传统方法，对 PE 的免疫大鼠模型中的转运体变化进行了特征描述，以确定其在未来药物处置研究中的实用性和预测价值。PE 通过在妊娠第 13-16 天每天给大鼠低剂量内毒素（0.01-0.04mg/kg）诱导，收集尿液，并在妊娠第 17 天或第 18 天处死大鼠。PE 大鼠与 PE 患者具有相似的表型，包括蛋白尿和肿瘤坏死因子和白细胞介素 6 水平升高。PE 大鼠胎盘组织中 Bcrp 的转录和蛋白水平在妊娠第 18 天显著下调。PE 时多药耐药蛋白 1a、多药耐药蛋白 1b 和有机阴离子转运蛋白 2B1mRNA 也减少。蛋白质组学揭示了各种 PE 的特征，包括免疫激活、氧化应激、内质网应激和细胞凋亡。总之，我们的研究结果表明，免疫性 PE 大鼠模型与人 PE 具有许多相似之处，同时胎盘转运体也发生失调。因此，该模型可能有助于研究 PE 对母体和胎儿 BCRP 底物处置的影响。意义陈述：充分描述疾病的临床前模型对于确定其对人类疾病的有效性是必要的。我们结合传统和蛋白质组学方法对模型进行了特征描述，确定了我们的 PE 模型与人类疾病之间存在许多表型相似之处。与人类病理生理变化的一致性使得更有信心使用这种临床前模型。
