酮康唑对健康成人肝细胞微粒体细胞色素P450同工酶3A4、1A2活性的作用  

Effect of ketoconazole on the activity of CYP4503A4 and CYP450 1A2 of hepatic microsomes in healthy adults

作　　者：杨贵忠[1] 袁野[1] 周岐新[1] 杨俊卿 刘颖菊[1] 

机构地区：[1]重庆医科大学基础医学院药理教研室,重庆400016

出　　处：《南方医科大学学报》2008年第9期1634-1635,1639,共3页Journal of Southern Medical University

基　　金：国家自然科学基金(30572353);重庆医科大学校际合作课题

摘　　要：目的观察酮康唑对健康成人肝细胞微粒体细胞色素P450同工酶3A4、1A2活性的作用,为临床上安全有效地联合用药提供实验依据。方法采用健康成人肝细胞微粒体,分为对照组和处理组。酮康唑处理组分别加入不同浓度的酮康唑1 ml,对照组仅加入培养液,孵育15 min后再加入CYP450同工酶3A4和1A2的相应底物(分别为睾酮和非那西丁)再孵育20 min。反应终止后用高效液相色谱仪测量代谢产物(分别为6β-羟基睾酮与对乙酰氨基酚)的生成量,分别代表3A4和1A2的活性。结果细胞色素P450同工酶3A4的相对活性百分比减小到对照组50%时(IC50)酮康唑的质量浓度为0.16 mg/L。而同工酶3A4的相对活性百分比随质量浓度酮康唑增加逐渐减小,各处理组与对照组比较差异均有显著性意义(P<0.05)。低剂量细胞色素P450同工酶1A2的相对活性百分比处理组与对照组比较明显降低(P<0.05),高剂量细胞色素P450同工酶1A2的相对活性百分比处理组与对照组比较则明显升高(P<0.05)。结论酮康唑对健康成人肝细胞微粒体细胞色素P450同工酶3A4的活性有抑制作用,然而对细胞色素P450同工酶1A2的活性则是低剂量有抑制作用,而高剂量有诱导作用。Objective To observe the effect ofketoconazole on the activity ofcytochrome P450 （CYP） 1A2 and 3A4 in hepatic microsomes of healthy adults. Methods Human hepatic microsomes obtained fom healthy adults were randomly divided into control group and ketoconazole-treatment groups at different concentrations. Atter 15 min of culture, the substrates （testosterone for CYP3A4 and phenacetin for CYP1A2） were added and incubated for another 20 min. The metabolites （6-testosterone and acetaminophen） were then measured with high-performance liquid chromatography （HPLC） to assess the activities of CYP3A4 and 1A2. Results Significant difference was found between the groups in the quantity of 6-testosterone and the relative activity of CYP3A4 （P〈0.05）. The IC5o ofketoconazole for CYP3A4 was 0. 16 mg/L. Both the quantity of 6-testosterone and the relative activity of CYP3A4 were reduced gradually with the increment of ketoconazole concentration. Significant differences were found between the ketoconazole groups and the control group in both the quantity of acetaminophen and the relative activity of CYP 1 A2 （P〈0.05）. Ketoconazole at low doses reduced CYP 1 A2 activity and but increased the activities at high doses （P〈0.05）. Conclusion In the range of maximum clinical blood concentration, ketoconazole can inhibit the activity of CYP3A4, but not that of CYP1A2, in the hepatic microsomes in healthy adults.

关 键 词：酮康唑 健康成人肝细胞微粒体 CYP3A4 CYP1A2 细胞色素P450 

分 类 号：R96[医药卫生—药理学]