摘要
目的对比测定贵州小型香猪与人肝微粒体细胞色素CYP酶的五个主要亚型的活性,并对二者活性相似的亚型以特异性抑制剂进行抑制,观察抑制活性反应的相似性,比较二者的CYP酶特性,评估贵州小型香猪作为人体外药物代谢动力学研究实验动物模型的可行性及其可应用的药物代谢反应类型。方法制备贵州小型香猪和人的肝微粒体,构建肝微粒体和探针底物的反应体系以及抑制剂抑制反应的体系,利用HPLC测定CYP3A,CYP1A,CYP2A,CYP2D和CYP2E酶的探针底物与肝微粒体反应的活性,并对贵州小型香猪和人的相应活性值进行比较,选择活性最为相近的亚型进行特异性抑制。结果贵州小型香猪肝微粒体具有CYP酶的五个主要亚型的反应活性,其中CYP3A酶的两个特异反应即硝苯地平氧化反应,睾酮6β-羟化反应的活性值和人肝的相应活性接近。同时,二者的CYP3A酶的特异性抑制反应相似。结论贵州小型香猪适用于作为人的CYP3A酶及其相关药物代谢研究的良好动物模型。鉴于CYP3A酶是人体内Ⅰ相反应最主要的药物代谢酶,因此贵州小型香猪作为人体药代动物模型具有一定前景。
Objective To evaluate the feasibility of Guizhou minipig to be used as a model in research on pharmacokinetic properties of CYPs in human by comparing the biotransformation activity in liver microsomes of Guizhou minipig and human analogs. Methods To prepare Guizhou minipig and human liver microsomes and to establish incubation mixtures and the chemical inhibitory methods. To use probe substrates specific for human CYP3A, CYP1A, CYP2A, CYP2D and CYP2E to evaluate the biotransformation activity in the minipig liver microsomes and compared with those of human analogs. To observe the inhibitory effects by using chemical inhibitor specific to the most similar CYP isozyme. Results Five of the main CYP reactions were found in Guizhou minipig liver microsomes. Comparable levels of nifedipine oxidation and testosterone 6β-hydroxylation activity were observed in the minipig and human liver microsomes. Their inhibitory effects were also similar. Conclusion It seemes that human CYP3A may be well modeled by Guizhou minipig liver mierosomes. Since CYP3A is the most important enzyme in drug metabolism in human, it would be promising to use Guizhou minipig as a model for research on pharmaeokineties and toxicological properties of CYPs in human.
出处
《中国比较医学杂志》
CAS
2006年第3期157-161,共5页
Chinese Journal of Comparative Medicine
基金
国家"十五"科技攻关计划重点项目(2004BA717B-3)资助
作者简介
李健（1981-）,女,硕士生,研究方向：医学实验动物学.
通讯作者
通讯作者
