用于药物研发的细胞色素P450酶3A4体外肝细胞模型的研究进展  

Progress in CYP3A4-expressionin vitro liver cellular models for drug testing

作　　者：饶小惠[1,2] 陈锋[1,2] 潘明新[1,2] 汪艳[1,2] 

机构地区：[1]南方医科大学珠江医院再生医学研究所,广东广州510280 [2]南方医科大学珠江医院肝胆二科,广东广州510280

出　　处：《中国药理学与毒理学杂志》2013年第6期1043-1048,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(31100701);高等学校博士学科点专项科研基金(20114433120001)~~

摘　　要：药物研发中生理性功能的体外细胞模型是非常重要的。细胞色素P450酶3A4(CYP3A4)是最重要的临床药物代谢酶之一,其作用底物谱广泛。相应地由这些底物作用于CYP3A4酶而产生的酶活性被抑制或诱导,直观表现为复杂化的药物代谢相互作用。因此,CYP3A4体外细胞模型在药物研发过程中具有重要应用价值。目前常用CYP3A4表达的一些体外模型,相比体内有不同程度的差距。这些差距有望通过加深机制了解、基因工程学技术以及体外微环境模拟功能单元构建组织工程技术的进步,而逐步得以缩减或消除。如何构建接近生理性表达的体外CYP3A4细胞模型是本研究领域一直探索的热点。本文就目前已知的CYP3A4生理功能特征、表达调控机制以及基于已知相关机制研究进行体外细胞模型构建的细胞种类、构建策略和方式进行综述。Physiologically-functionalized in vitro cellular models are valuable for the research and development of new drugs. Cytochrome P450 3A4 （CYP3A4） is one among the most important enzymes for the metabolism analysis of drugs in clinical pharmacotherapy. Ways to develop the in vitro cell model that can reach to the performance levels of the in vivo cells mainly expressing CYP3A4 is a hot topic and has been explored with many efforts. The paper reviewed the general information of what has been understood about the physiological function and the expression regulation of the CYP3A4 molecule; and based on the mechanistic understanding, what types of cell model and the expression-modification of the cell models have been taken for analysis of the CYP3A4 metabolism of drugs; in addition some cases were also cited to illustrate the modification strategy and method. The current advances in the research of CYP3A4 show that there is significant variance among populations mainly due to the related extra-environmental cues or the genetic differences. CYP3A4 possesses a wide spectrum of working substrates, which can influence the expression and function of CYP3A4 at different molecular levels and contribute to the intuitive phenomena of induction or inhibition of the enzyme function, and then the consequently complicated drug-drug interactions. The cell models now available for CYP3A4 metabolism analysis can be roughly classified into the non-hepatic and the hepatic cell models; or the expression gene-and the regulatory gene-modification cell models. Currently all of the reported models still cannot reach to the same contents and levels as those of the physiological counterpart, the primary human hepatocytes. However, with the progress in understanding of the basic mechanism of CYP3A4 expression and the rapid improvement in the biotechnologies such as genetic cellular and tissue engineering, the gap would become narrow down and finally eliminate in the future. The paper reviewed the general information of what has been unders

关 键 词：细胞色素P450 CYP3A4 肝细胞 体外 

分 类 号：R965.1[医药卫生—药理学]