慢性不可预见性温和应激模型大鼠的肝脏药物代谢酶活性变化研究

Study of change in activity of hepatic drug metabolism enzymes in rat model of chronic unpredictable mild stress

采用鸡尾酒(cocktail)探针药物法研究慢性不可预见性温和应激(chronic unpredictable mild stress,CUMS)造成的抑郁状态对大鼠体内6种CYP450亚酶活性的影响。根据Katz法建立CUMS大鼠抑郁模型;分别选用甲苯磺丁脲、氯唑沙宗、茶碱、咪达唑仑、奥美拉唑及右美沙芬作为大鼠CYP2C6、CYP2E1、CYP1A2、CYP3A2、CYP2D1、CYP2D2的探针底物,采用液质联用法(LC-MS/MS)测定对照组与模型组大鼠体内6种混合探针的血药浓度,计算药动学参数。结果表明,茶碱和氯唑沙宗代谢显著加快(P<0.01),甲苯磺丁脲、右美沙芬、奥美拉唑、咪达唑仑的代谢无显著差异。结果说明,慢性不可预见性温和应激造成的抑郁状态对CYP1A2有强诱导、对CYP2E1有中强诱导作用。

This study aimed to explore the impact of depression caused by chronic unpredictable mild stress （CUMS） on in vivo activity of six kinds of CYP450 isoforms in rats. According to ‘Katz＇ method, the model of CUMS was established. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan were chosen as probe substrates ofCYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1 and CYP2D2 of rats. Plasma concentration of six kinds of CYP450 in control group and model group were determined by LC-MS/MS and computed pharmacokinetic parameters. Consequently, metabolism of theophylline and chlorzoxazone accelerated significantly （P〈0.01）, but tolbutamide, dextromethorphan, omeprazole and midazolam had no significant difference. The present study proved that depression caused by CUMS had strong induction to CYP1A2 and medium induction to CYP2E1.