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目的研究吡咯里嗪类ML-3000及其两种NO供体衍生物ML-4000和ML-5000对人P450同工酶CYP2D6、CYP1A2、CYP2C9、CYP2C19和CYP3A4的体外抑制作用。方法采用Gentest公司的高通量P450酶抑制剂筛选试剂盒(High throughput Inhibitor Screening Kit),测定ML-3000、ML-4000和ML-5000对五种P450同工酶CYP2D6、CYP1A2、CYP2C9、CYP2C19和CYP3A4的体外抑制作用。结果 ML-3000、ML-4000和ML-5000抑制CYP3A4的IC50分别为7.07、0.40、2.82μmol/L,对其他4个酶(CYP1A2、CYP2D6、CYP2C9和CYP2C19)的IC50均大于10μmol/L。结论 3种化合物对CYP3A4活力均有抑制作用,其中ML-4000的抑制能力最强。3种化合物对其他4个酶基本没有抑制作用。
Objective To investigate the inhibitory effects of pyrrolizine ML-3000 and its two NO donor derivatives ML-4000 and ML-5000 on human P450 isoenzyme CYP2D6, CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in vitro. Methods High-throughput P450 Enzyme Inhibitor Screening Kit from Gentest was used to determine the effects of ML-3000, ML-4000 and ML-5000 on five P450 isozymes CYP2D6, CYP1A2, CYP2C9, CYP2C19 and CYP2C19 In vitro inhibition of CYP3A4. Results The IC50 of CYP3A4 in ML-3000, ML-4000 and ML-5000 were 7.07,0.40 and 2.82μmol / L, respectively. The IC50 values of other four enzymes (CYP1A2, CYP2D6, CYP2C9 and CYP2C19) were all greater than 10μmol / L. Conclusion All three compounds have inhibitory effects on the activity of CYP3A4, of which ML-4000 has the strongest inhibitory effect. The three compounds had no inhibitory effect on the other four enzymes.