糖尿病状态下Caco-2细胞CYP3A4和P-gp功能的变化及其机制研究
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篇名: 糖尿病状态下Caco-2细胞CYP3A4和P-gp功能的变化及其机制研究
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摘要: 目的:考察糖尿病状态下Caco-2细胞色素P450(CYP)3A4和P糖蛋白(P-gp)功能的变化及其机制。方法:分别在Caco-2细胞中加入25、50、100 μmol/L咪达唑仑(CYP3A4探针底物)温孵15、30、60、120、180 min,加入0.1、0.2、0.4 μg/ml罗丹明123(P-gp底物)温孵15、30、60、90、120 min,以确定底物浓度及温孵时间;在Caco-2细胞中加入不同浓度胰岛素、葡萄糖和脂肪酸(软脂酸和油酸)后测定咪达唑仑的代谢产物1′ -OH咪达唑仑的生成量和罗丹明123的摄取量,以考察对细胞CYP3A4和P-gp功能的影响。结果:底物浓度分别为咪达唑仑50 μmol/L、罗丹明123 0.1 μg/ml,均温孵2 h。随着胰岛素、葡萄糖、软脂酸浓度的升高,1′ -OH咪达唑仑的生成量降低,CYP3A4活性降低;罗丹明123的摄取增加,P-gp外排功能降低。油酸对1′ -OH咪达唑仑的生成量和罗丹明123的摄取量没有显著影响。结论:糖尿病状态下,胰岛素、葡萄糖和软脂酸水平的升高均可降低CYP3A4和P-gp的功能,但油酸对CYP3A4和P-gp的功能影响不大。
ABSTRACT: OBJECTIVE: To investigate the function change of intestinal CYP3A4 and P-glycoprotein (P-gp) under diabetic conditions and its mechanism. METHODS: Caco-2 cells were respectively added with 25, 50 and 100 μmol/L midazolam (CYP3A4 probe substrate) for incubation for 15, 30, 60, 120, 180 min; with 0.1, 0.2, 0.4 μg/ml rhodamine 123 (P-gp substrate) for incubation for 15, 30, 60, 90, 120 min to determine the substrate concentrations and incubation time. Caco-2 cells were added with insulin, glucose and fatty acid (palmitic acid and oleic acid) at different concentrations, and then the production of 1′ -OH-midazolam, the metabolite of midazolam, and the intake of rhodamine 123 were determined, in order to investigated the effect on the function of CYP3A4 and P-gp. RESULTS: The optimal substrate concentrations and incubation time were as follows as 50 μmol/L midazolam, 0.1 μg/ml rhodamine 123 and incubation for 2 h. With the increase in the concentration of insulin, glucose and palmitic acid, the production of 1′ -OH-midazolam and the activity of CYP3A4 reduced; the intake of rhodamine 123 increased, and the efflux transport function of P-gp decreased. Oleic acid had no significant effect on the production of 1′ -OH-midazolam or the intake of rhodamine 123. CONCLUSIONS: Under diabetes condition, the increase of insulin, glucose and palmitic acid may reduce the function of CYP3A4 and P-gp, while oleic acid has no effect on the function.
期刊: 2016年第27卷第25期
作者: 邹素兰,胡楠
AUTHORS: ZOU Sulan,HU Nan
关键字: 糖尿病;Caco-2细胞;CYP3A4;P糖蛋白;胰岛素;葡萄糖;脂肪酸;体外试验
KEYWORDS: Diabetes; Caco-2 cells; CYP3A4; P-glycoprotein; Insulin; Glucose; Fatty acid; in vitro test
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