摘要
目的:探讨链脲佐菌素(STZ)诱导糖尿病模型大鼠体内细胞色素P450酶(CYPs)6种亚型活性及蛋白含量的变化,为临床合理用药提供参考。方法:将大鼠随机分为空白对照组、糖尿病1周组、4周组和8周组。应用"Cocktail"探针药物法评价各组大鼠血浆中各探针药物的浓度,比较空白对照组和3组糖尿病模型组各探针药物的药动学参数,评价糖尿病大鼠体内细胞色素P450酶亚型1A2、2D6、2C19、2C9、2E1和3A4活性的变化;选择酶联免疫吸附测定法(ELISA)检测糖尿病大鼠肝脏中此6种CYPs亚型酶蛋白相对表达量的变化。结果:相比于空白组,糖尿病4周和8周组大鼠体内咖啡因AUC分别降低了62.78%和79.31%(P<0.01),校正后的清除率(CLZ)分别升高了5.12和52.35倍(P<0.05,P<0.01);糖尿病模型组大鼠体内美托洛尔AUC、t1/2z和CLZ均无显著变化;糖尿病8周大鼠体内氯唑沙宗AUC降低了60.58%(P<0.01),CLZ升高了1.2倍(P<0.01);糖尿病4周和8周组大鼠体内奥美拉唑AUC降低了55.60%和81.42%(P<0.05,P<0.01),CLZ升高了27.50和41.25倍(P<0.01);8周大鼠甲苯磺丁脲AUC降低了45.39%(P<0.05)、CLZ升高了83.33%(P<0.01);糖尿病1周和8周组大鼠体内咪达唑仑AUC降低了43.23%和53.87%(P<0.05,P<0.01),CLZ升高了1.33和2.04倍(P<0.05)。相比于空白组,糖尿病1周和4周组大鼠肝脏中CYP1A2蛋白相对表达量升高了24.60%和26.41%(P<0.05),糖尿病1周组大鼠CYP3A4蛋白相对表达量降低了24.62%(P<0.05),CYP2D6、2E1、2C19和2C9蛋白相对表达量无变化。结论:与空白组相比,糖尿病模型组大鼠体内CYP1A2、2E1、2C19、2C9和3A4活性均被诱导,而CYP2D6活性未发生变化;与空白组相比,糖尿病1周、4周组的大鼠肝脏中CYP1A2蛋白相对表达量明显升高,糖尿病1周组大鼠肝脏中CYP3A4蛋白相对表达量明显降低,CYP2D6、2E1、2C9和2C19亚型酶蛋白相对表达量均未发生显著变化。
Objective: To investigate the variations of metabolic activities and protein expression of CYP450 isoforms in streptozotocin( STZ)-induced diabetic rats,providing a guide for clinical treatment of diabetics. Methods Rats were randomly divided into four groups: one control group and three experimental groups( rats with one-weeked,four-weeked and eight weeked diabetes,respectively). The variations of metabolic activities and protein expression of CYP450 isoforms in different groups were evaluated by comparing plasma concentrations,the pharmacokinetic parameters and protein levels with Cocktail approach. Results: In the the rats with eight-weeked diabetes,AUC of caffeine,chlorzoxazone,omeprazole,tolbutamide and midazolam decreased by79. 31%,60. 58%,81. 42%,45. 39% and 53. 87%,respectively and CLz of these probes increased by 52. 35,1. 2,41. 25,2. 04 times and 83. 33%,respectively,compared with those in the control group. In the rats with four-weeked diabetes,AUC of caffeine and omeprazole decreased by 62. 78% and 55. 60%,respectively and CLz increased by 5. 12 and 27. 50 times than those in the control group,respectively. There were no significant differences in pharmacokinetic parameters of metoprolol in all diabetic groups. Compared with the control group,the protein contents of CYP1 A2 in one-weeked and four-weeked diabetes groups increased by 24. 60% and 26. 41%,respectively while the protein content of CYP3 A4 in one-weeked group decreased by 24. 62%.No difference was found in the protein levels of CYP2 D6,CYP2 E1,CYP2 C19 and CYP2 C9 among all the groups. Conclusions:The metabolic activities of CYP1 A2,2 E1,2 C19,2 C9 and 3 A4 were induced in diabetic groups; the protein level of CYP1 A2 in one-and four-weeked diabetes group increased,respectively but CYP3 A4 in one-weeked diabetes group decreased,and CYP2 D6,2 E1,2 C19 and 2 C9 in all the groups were not changed.
出处
《天津药学》
2017年第5期1-8,共8页
Tianjin Pharmacy
作者简介
通讯作者：娄建石,E-mail：jianshilou＠163.com.
