P-糖蛋白诱导作用的研究进展

◢ 中国药科大学学报, 2018, 49(1): 26-33. DOI: 10.11665/j.issn.1000-5048.20180104

许悦^1,2,  陈根富²,  熊涛²,  彭英¹,  阮婷婷^1,2,  王广基¹,  孙建国¹

¹ 中国药科大学药物代谢动力学重点实验室

² 上海药明康德新药开发有限公司药性评价部

摘要:

P-糖蛋白(P-gp)是ATP结合盒转运体家族中重要的外排转运体。诱导作用可上调细胞外排转运体的表达并增强其功能，从而减少外源性有害异物造成的伤害，对维持细胞内环境稳态有重要作用。本文结合课题组的研究，综述了近年来P-gp的诱导模型、实验方法及其在新药研究中的应用。重点总结了多种P-gp的体外细胞诱导模型和体内动物诱导模型，检测P-gp基因、蛋白表达水平和外排转运功能的实验方法，以及P-gp与代谢酶、其他转运体的共同调节作用。同时介绍了以P-gp诱导进行临床解毒治疗的策略以及计算机辅助设计的P-gp诱导药效基团模型。本综述为临床前药物设计、新合成化合物诱导活性的筛选和潜在临床药物相互作用的预测提供一定的指导。

关键词: 

P-糖蛋白  /  诱导  /  细胞模型  /  解毒作用  

Abstract:

P-glycoprotein(P-gp)is an important efflux protein of ATP-binding cassette transporter superfamily. Cells could be protected from detrimental xenobiotics by the up-regulation of efflux pumps. In this review, an extensive literature search for P-gp induction research was conducted, and a focus was brought onto the P-gp induction models, experiment methods and its applications in drug discovery. We mainly introduced the in vitro cell-based models and in vivo rodent animal models for induction research, methods that investigate induction potency by detecting the protein, gene expression and efflux function, as well as co-regulation between P-gp and other transporters or drug metabolism enzymes. P-gp induction can serve as a clinical therapeutic strategy by reducing the intracellular concentration of deleterious xenobiotics significantly, and the in silico P-gp induction pharmacophore model was also discussed. This review could be of great importance for pre-clinical drug design, the screening of new synthesized compounds and the prediction of potential clinical drug-drug interactions.

Keywords: 

P-glycoprotein  /  induction  /  cell model  /  antidotal effect