Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada.
CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada.
Int J Mol Sci. 2019 Jul 2;20(13):3257. doi: 10.3390/ijms20133257.
To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with ( = 20) or without ( = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein min) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D ( > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.
为了研究 2 型糖尿病（T2D）对人十二指肠活检中 10 种细胞色素 P450（CYP450）、两种羧酸酯酶和三种药物转运体（ABCB1、ABCG2、SLCO2B1）mRNA 表达水平的影响，并比较 T2D 患者和非 T2D 患者十二指肠活检中 4 种 CYP450 同工酶的药物代谢酶活性。从接受计划的胃肠内窥镜检查的 T2D 患者（n=20）或非 T2D 患者（n=16）中获取人十二指肠活检，通过 RT-qPCR 定量测定其 mRNA 水平。用探针底物孵育活检匀浆后，测定 CYP450 活性，探针底物分别为 CYP2B6（丁丙诺啡）、CYP2C9（甲苯磺丁脲）、CYP2J2（依巴斯汀）和 CYP3A4/5（咪达唑仑）。研究了与炎症、T2D、人口统计学和遗传学相关的协变量。T2D 对评估的所有酶和转运体的 mRNA 水平没有产生重大影响。用 LC-MS/MS 测定的 CYP2C9（0.48±0.26 对 0.41±0.12）、CYP2J2（2.16±1.70 对 1.69±0.93）和 CYP3A（5.25±3.72 对 5.02±4.76）代谢产物的形成率在 T2D 患者和非 T2D 患者的活检之间没有差异（>0.05）。未测量 CYP2B6 特异性活性。T2D 患者的 TNF-α 水平较高，但与十二指肠中药物代谢酶或转运体的 mRNA 表达水平变化无关。T2D 未调节人十二指肠中测试的药物代谢酶和转运体的表达或活性。先前报道的 T2D 患者药物口服清除率的变化可能是由于肝脏和/或肠道其他部位的组织特异性疾病调节所致。
