PXR介导的CYP3A抑制中的磷酸化和蛋白质-蛋白质相互作用。
Phosphorylation and protein-protein interactions in PXR-mediated CYP3A repression.
作者信息
Pondugula Satyanarayana R, Dong Hanqing, Chen Taosheng
机构信息
St. Jude Children's Research Hospital, Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, USA.
出版信息
Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):861-73. doi: 10.1517/17425250903012360.
BACKGROUND
The expression of drug-metabolizing enzymes CYPs is controlled by pregnane X receptor (PXR), and, therefore, understanding how PXR modulates CYP expression is important to minimize adverse drug interactions, one type of preventable adverse drug reaction.
OBJECTIVE
We review the mechanisms of PXR-mediated repression of CYP expression.
METHODS
We discuss the clinical implications of CYP repression and the role of signal cross-talks, including protein-protein interactions and phosphorylation of PXR and coregulators, in inhibiting PXR and repressing CYP expression.
RESULTS/CONCLUSION: Kinases such as cyclin-dependent kinase 2, protein kinase A, PKC and 70 kDa form of ribosomal protein S6 kinase repress CYP expression by phosphorylating and inhibiting PXR. Growth factor signaling represses CYP expression by phosphorylating and inhibiting forkhead in rhabdomyosarcoma, a co-activator of PXR. During inflammation, NF-kappaB represses both PXR and CYP expression through protein-protein interactions with the PXR pathway.
背景
药物代谢酶细胞色素P450（CYPs）的表达受孕烷X受体（PXR）调控，因此，了解PXR如何调节CYP表达对于最大限度减少药物不良相互作用（一种可预防的药物不良反应）至关重要。
目的
我们综述PXR介导的CYP表达抑制机制。
方法
我们讨论CYP抑制的临床意义以及信号串扰的作用，包括蛋白质-蛋白质相互作用以及PXR和共调节因子的磷酸化，这些在抑制PXR和CYP表达中发挥作用。
结果/结论：诸如细胞周期蛋白依赖性激酶2、蛋白激酶A、蛋白激酶C和核糖体蛋白S6激酶70 kDa形式等激酶通过磷酸化和抑制PXR来抑制CYP表达。生长因子信号传导通过磷酸化和抑制横纹肌肉瘤中的叉头框蛋白（一种PXR的共激活因子）来抑制CYP表达。在炎症过程中，核因子κB通过与PXR途径的蛋白质-蛋白质相互作用来抑制PXR和CYP表达。
Zotero 插件