Liao Michael Z, Gao Chunying, Bhatt Deepak Kumar, Prasad Bhagwat, Mao Qingcheng
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington DC, 98195, United States.
Drug Metab Lett. 2018;12(2):145-152. doi: 10.2174/1872312812666180625122810.
Few studies have systematically investigated pregnancy-induced changes in protein abundance of drug transporters in organs important for drug/xenobiotic disposition.
The goal of this study was to compare protein abundance of important drug/xenobiotic transporters including Abcb1a, Abcg2, Abcc2, and Slco1b2 in the liver, kidney and brain of pregnant mice on gestation day 15 to that of non-pregnant mice.
The mass spectrometry-based proteomics was used to quantify changes in protein abundance of transporters in tissues from pregnant and non-pregnant mice.
The protein levels of hepatic Abcc2, Abcc3, and Slco1a4 per μg of total membrane proteins were significantly decreased by pregnancy by 24%, 72%, and 70%, respectively. The protein levels of Abcg2, Abcc2, and Slco2b1 per μg of total membrane proteins in the kidney were significantly decreased by pregnancy by 43%, 50%, and 46%, respectively. After scaling to the whole liver with consideration of increase in liver weight in pregnant mice, the protein abundance of Abcb1a, Abcg2, Abcc2, Abcb11, Abcc4, Slco1a1, and Slco1b2 in the liver was ~50-100% higher in pregnant mice, while those of Abcc3 and Slco1a4 were ~40% lower. After scaling to the whole kidney, none of the transporters examined were significantly changed by pregnancy. Only Abcg2 and Abcb1a were quantifiable in the brain and their abundance in the brain was not influenced by pregnancy.
Protein abundance of drug transporters can be significantly changed particularly in the liver by pregnancy. These results will be helpful to understand pregnancy-induced changes in drug/xenobiotic disposition in the mouse model.
很少有研究系统地调查过妊娠对药物/外源性物质处置重要器官中药物转运蛋白丰度的影响。
本研究旨在比较妊娠第15天的妊娠小鼠与未妊娠小鼠肝脏、肾脏和大脑中重要药物/外源性物质转运蛋白（包括Abcb1a、Abcg2、Abcc2和Slco1b2）的蛋白丰度。
采用基于质谱的蛋白质组学技术定量妊娠和未妊娠小鼠组织中转运蛋白的蛋白丰度变化。
每微克总膜蛋白中，肝脏Abcc2、Abcc3和Slco1a4的蛋白水平因妊娠分别显著降低24%、72%和70%。每微克总膜蛋白中，肾脏Abcg2、Abcc2和Slco2b1的蛋白水平因妊娠分别显著降低43%、50%和46%。考虑到妊娠小鼠肝脏重量增加，按全肝计算，妊娠小鼠肝脏中Abcb1a、Abcg2、Abcc2、Abcb11、Abcc4、Slco1a1和Slco1b2的蛋白丰度高出约50 - 100%，而Abcc3和Slco1a4的蛋白丰度则低约40%。按全肾计算，所检测的转运蛋白均未因妊娠而发生显著变化。只有Abcg2和Abcb1a在大脑中可定量，且其在大脑中的丰度不受妊娠影响。
妊娠可显著改变药物转运蛋白的蛋白丰度，尤其是在肝脏中。这些结果将有助于理解小鼠模型中妊娠引起的药物/外源性物质处置变化。
