Car受体激活对妊娠小鼠药物处置基因表达的调控。

A. Bright, G. Herrera-Garcia, Jamie E. Moscovitz, D. You, G. Guo, L. Aleksunes
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引用次数: 6

摘要

超过一半的孕妇使用处方药,以维持母体和胎儿的健康。组成型雄甾受体(Car)通过调节编码代谢酶和转运蛋白的基因的转录,对化学物质的处置产生重要影响。然而,Car激活对怀孕期间化学处置的影响尚不清楚。本研究旨在确定妊娠在何种程度上改变药物代谢酶和转运蛋白的表达,以响应Car的药理激活。为了验证这一点,怀孕的C57BL/6小鼠在妊娠第14、15和16天被给予IP剂量的载体或强效Car激动剂TCPOBOP。在妊娠第17天测定肝脏Car靶基因(ⅰ期、ⅱ期和转运体)mRNA和蛋白表达量。观察到妊娠相关的变化,如Cyp2b10、Ugt1a1和Sult1a1的诱导以及Ugt1a6、Gsta1、Gsta2和Mrp6的抑制。有趣的是,TCPOBOP对Cyp2b10、Gsta1、Gsta2和Mrp2-4 mrna的诱导作用在母体肝脏中减弱,这表明妊娠期间发生的生化和/或生理变化阻碍了Car的激活。综上所述,这些发现表明妊娠和Car的药理激活可以不同地调节药物代谢和转运基因的表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Regulation of Drug Disposition Gene Expression in Pregnant Mice with Car Receptor Activation.
More than half of pregnant women use prescription medications in order to maintain both maternal and fetal health. The constitutive androstane receptor (Car) critically affects the disposition of chemicals by regulating the transcription of genes encoding metabolic enzymes and transporters. However, the effects of Car activation on chemical disposition during pregnancy are unclear. This study aims to determine the degree to which pregnancy alters the expression of drug metabolizing enzymes and transporters in response to the pharmacological activation of Car. To test this, pregnant C57BL/6 mice were administered IP doses of vehicle, or a potent Car agonist, TCPOBOP, on gestation days 14, 15 and 16. Hepatic mRNA and protein expression of Car target genes (phase I, II and transporters) were quantified on gestation day 17. Pregnancy-related changes, such as induction of Cyp2b10, Ugt1a1 and Sult1a1 and repression of Ugt1a6, Gsta1, Gsta2 and Mrp6, were observed. Interestingly, the induction of Cyp2b10, Gsta1, Gsta2 and Mrp2-4 mRNAs by TCPOBOP was attenuated in maternal livers suggesting that Car activation is impeded by the biochemical and/or physiological changes that occur during gestation. Taken together, these findings suggest that pregnancy and pharmacological activation of Car can differentially regulate the expression of drug metabolism and transport genes.
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