Maximos Sarah, Chamoun Michel, Gravel Sophie, Turgeon Jacques, Michaud Veronique
Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.
Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
Pharmaceutics. 2017 Sep 26;9(4):40. doi: 10.3390/pharmaceutics9040040.
Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals ( = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes. Expression levels of cyp3a11 and cyp3a25 mRNA were decreased in the liver (>2-14-fold) and kidneys (>2-fold) of HFD groups which correlated with a significant reduction in midazolam metabolism (by 21- and 5-fold in hepatic and kidney microsomes, respectively, < 0.001). HFD was associated with decreased activities of cyp2b and cyp2c subfamilies in all organs tested except in the kidneys (for tolbutamide). Other cyp450 hepatic activities were minimally or not affected by HFD. Taken together, our data suggest that substrate-dependent and tissue-dependent modulation of cyp450 metabolic capacities by early phases of T2D are observed, which could modulate drug disposition and pharmacological effects in various tissues.
多种疾病，如2型糖尿病（T2D），可能会改变药物清除率。本研究的目的是使用高脂饮食（HFD）作为C57BL6小鼠肥胖相关性糖尿病的模型，评估T2D对CYP450表达和活性的影响。测定了HFD处理动物（n = 45）肝脏和肝外组织（肾脏、肺和心脏）中15种不同亚型的cyp450 mRNA表达水平。使用8种已知的特定人类直系同源CYP450亚型底物评估HFD对cyp450代谢活性的调节：对肝脏和肝外微粒体进行体外孵育。HFD组肝脏（>2至14倍）和肾脏（>2倍）中cyp3a11和cyp3a25 mRNA表达水平降低，这与咪达唑仑代谢显著降低相关（肝脏和肾脏微粒体中分别降低21倍和5倍，P < 0.001）。除肾脏外（对于甲苯磺丁脲），HFD与所有测试器官中cyp2b和cyp2c亚家族的活性降低有关。其他cyp450肝脏活性受HFD影响最小或未受影响。综上所述，我们的数据表明，在T2D早期阶段观察到了cyp450代谢能力的底物依赖性和组织依赖性调节，这可能会调节药物在各种组织中的处置和药理作用。
