人类细胞色素P450s研究概况及其在新药安全性评价中的应用  

Research Advances in Human Cytochrome P450s and their Application in New Drug Evaluation

作　　者：马璟[1] 钱蓓丽[1] 

机构地区：[1]上海医药工业研究院国家上海新药安全评价研究中心,上海201203

出　　处：《中国新药杂志》2002年第1期36-42,共7页Chinese Journal of New Drugs

摘　　要：人类细胞色素P45 0s(CYP45 0s)对许多内源、外源性化合物在体内的I相生物转化有重要作用。人类编码CYP45 0s的基因已基本明确 ,为 5 5个基因 ,2 9个假基因。目前欧美各国已经把CYP45 0s及其同工酶测定用于新药的筛选及安全性评价。本实验室建立了不同种属动物肝细胞色素P45 0s同工酶的测定方法 ,并选择来氟米特、重组人白细胞介素 11(rhIL 11)及重组人表皮生长因子 (rh EGF) ,检测其对不同动物CYP45 0s的影响。实验结果表明 :①来氟米特对Beagle犬肝微粒体蛋白含量、CYP45 0s总量、7 乙氧基试卤灵脱乙基酶 (CYP1A1)、香豆素 7 羟化酶 (CYP2A6 /CYP2A2 )、甲苯磺丁脲羟化酶 (CYP2C8/9)、氯唑沙宗羟化酶 (CYP2E1)的比活性均无明显影响。②大鼠皮下注射rhIL 11后 ,肝微粒体中CYP1A1及CYP2A2比活性明显低于对照组 ,而肝微粒体蛋白含量、CYP45 0总量及CYP2E1比活性无明显变化。③rh EGF对猕猴肝微粒体蛋白含量、CYP45 0s总量、CYP1A1、CYP2A6、CYP2C8/9、S (+) 美芬妥英羟化酶 (CYP2C19)、丁呋洛尔 1 羟化酶 (CYP2D6 )、CYP2E1比活性均无明显影响。本实验建立的犬、大鼠及猴肝CYP45 0s测定方法具有快速、简单、重复性好等特点 ,可广泛用于药物筛选及临床前安全性评价。除合成药物外 。Cytochrome P450s (CYP450s) involved in the phase I metabolism of a variety of chemically diverse substances ranging from endogenous compounds to xenobiotics. Up to date,55 sequenced CYP genes and 29 pseudogenes were found in the human. In western countries CYP450s are estimated during new drug screening and safety evaluation. In this study, we established the methods for assaying the CYP450s in different animal liver microsomes to accelerate the discovery of new drugs. Based on the established methods, the effects of leflunomide,rh-IL11 and rh-EGF on CYP450s were evaluated. The results showed that no significant changes of the protein concentration and the total contents of cytochrome P450s in beagle dogs, rats and rhesus monkeys were observed at different sampling time.The specific activities of the CYP1A1, CYP2A6, CYP2C8/9 and CYP2E1 in beagle dogs were not changed after administration leflunomide.In rats, rh-IL11 had obvious inhibitory effect on the activities of the CYP1A1 and CYP2A2 but had no effect on the activities of the CYP2E1.The specific activities of the CYP1A1, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6 and CYP2E1 in rhesus monkeys were not changed after administration rh-EGF. The methods established for assaying cytochrome P450s activities in dogs, rats and monkeys liver microsomes in these studies were reproducible, simple and rapid, useful in early drug screening and safety evluation. For the new biotechnology derived drugs, we also should emphasize the importance of estimating the effects on CYP450s.

关 键 词：细胞色素P450s 同工酶 重组人白细胞介素-11 高效液相色谱 新药 安全性评价 动物实验 

分 类 号：R969[医药卫生—药理学] R965.3[医药卫生—药学]