甲基原薯蓣皂苷对人肝微粒体中7种CYP450酶活性的影响

目的研究甲基原薯蓣皂苷对CYP450酶的7种亚型酶活性的影响。方法将MPD和CYP450酶7种亚型的特异性探针底物咖啡因(CYP1A2)、右美沙芬(CYP2D6)、甲苯磺丁脲(CYP2C9)、s-美芬妥因(CYP2C19)、氯唑沙宗(CYP2E1)、香豆素(CYP2A6)及咪达唑仑(CYP3A4)与人肝微粒体进行孵化反应,采用HPLC和LC-MS/MS法测定对应的7种代谢产物(1,7-二甲基黄嘌呤、去甲右美沙芬、4-羟基甲苯磺丁脲、4-羟基美芬妥因、6-羟基氯唑沙宗、7-羟基香豆素和1-羟基咪达唑仑)的浓度,通过与对照组比较,确定MPD对以上7种酶活性的影响。结果MPD在1~10μmol.L-1时对7种酶均无明显抑制作用,在100μmol.L-1时对CYP2D6有抑制趋势,但对其他6种酶无抑制作用,均无统计学意义(P>0.05)。结论MPD在与以上6种酶(CYP1A2、CYP2E1、CYP2C19、CYP3A4、CYP2C9和CYP2A6)代谢的药物联合用药时,发生药物相互作用的可能性较小。

Effect of methyl protodioscin on seven cytochrome P450s activities in human microsomes

Objective To investigate the effect of methyl protodioscin (MPD) on seven cytochrome P450 enzymes in human liver microsome. Methods Seven probe drugs were incubated with or without methyl protodioscin respectively in human microsomes. The specific substrates used in this study were caffeine (CYP1A2), dextromethorphan (CYP2D6), tolbutamide (CYP2C9), (s)-mephenytoin (CYP2C19), chlorzoxazone (CYP2E1), coumarin (CYP2A6) and midazolam (CYP3A4). The concentrations of the substrate metabolites (paraxanthine, dextrorphan, 4-hydroxytolbutamide, 4-hydroxymephenytoin, 6-hydroxychlorzoxazone, 7-hydroxycoumarin and 1-hydroxymidazolam) were determined by HPLC and LC -MS/MS. Results MPD (1-10μmol&;#8226; L^-1) had no significant inhibition on the activities of the seven cytochrome P450 enzymes. MPD (100μmol&;#8226; L^-1) had inhibition tendency on the activity of CYP2D6 and no inhibition on the other six CYPs. No significant difference was observed (P>0.05) . Conclusion The probability of drug-drug interactions between MPD and other drugs, which are metabolized by the above six CYPs (CYP1A2, CYP2E1, CYP2C19, CYP3A4, CYP2C9 and CYP2A6), is very low.