对羟基苯甲酸丙酯和对羟基苯甲酸丁酯对人和大鼠肝微粒体CYP450酶活性的抑制作用

Inhibitory Effects of Propylparaben and Butylparaben on CYP450 Enzyme Activity in Human and Rat Liver Microsomes

本文目的是研究对羟基苯甲酸丙酯(羟苯丙酯;propylparaben,PP)和对羟基苯甲酸丁酯(羟苯丁酯;butylparaben,BP)对大鼠肝微粒体(rat liver microsomes,RLM)和人肝微粒体(human liver microsomes,HLM)细胞色素P450酶(cytochrome P450 enzyme,CYP)活性的抑制作用,并评价它们的相互作用潜能。在体外将系列浓度的羟苯丙酯和羟苯丁酯与大鼠和人肝微粒体孵育60 min,以非那西丁、安非他酮、甲苯磺丁脲、氯唑沙宗、香豆素、右美沙芬和咪达唑仑为CYP探针底物,应用质谱定量检测各探针底物的代谢产物生成量,计算得到IC_(50)和K_(i)值,评价2种化学受试物对大鼠和人肝微粒体CYP450酶的抑制活性和抑制类型,并对抑制强度进行分级。大鼠和人肝微粒体中羟苯丙酯是CYP1A2酶的中等强度抑制剂,羟苯丁酯在大鼠肝微粒体中是CYP1A2酶的弱抑制剂,在人肝微粒体中是CYP1A2酶的中等强度抑制剂,观察到对其他CYP450酶无抑制作用,这与用软件预测的羟苯丙酯和羟苯丁酯对CYP450酶的抑制种类结果一致,分子对接的结果也印证了羟苯丙酯和羟苯丁酯对CYP1A2酶活性的抑制作用,按照构效关系和同源CYP的物种敏感度预测模型,本文关于CYP的研究结果可以类推到其他哺乳动物和人类。

To investigate the inhibitory effects of propylparaben(PP)and butylparaben(BP)on cytochrome(CYP)P450 enzyme activity in rat liver microsomes(RLMs)and human liver microsomes(HLMs)and evaluate their interactional potentials,serial concentrations of PP and BP were incubated with RLMs or HLMs for 60 min in vitro.Phenacetin,bupropion,tolbutamide,chlorzoxazone,coumarin,dextromethorphan,and midazolam were used as CYP activity indicators.Metabolites were quantified by mass spectrometry;half maximal inhibitory concentration and inhibition constant were calculated to evaluate the effects and molds of PP and BP inhibitory activity on the CYP450 enzyme,which was graded by strength.PP was a moderate inhibitor of the CYP1A2 enzyme in RLMs and HLMs;BP was a weak inhibitor of the CYP1A2 enzyme in RLMs and a moderate inhibitor of the CYP1A2 enzyme in HLMs.Neither PP nor BP had inhibitory effects on other CYP450 enzymes,which is consistent with the software prediction results.According to the structure-activity relationship and the species sensitivity prediction model of homologous CYP enzymes,the results of these experiments may be generalizable to other mammals and humans.