Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers.
Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers.
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DOI：
10.7150/ijms.9866
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发表时间：
2014
影响因子：
3.6
通讯作者：
Mizuno S
中科院分区：
文献类型：
--
作者：
Kawauchi S;Nakamura T;Yasui H;Nishikawa C;Miki I;Inoue J;Horibe S;Hamaguchi T;Tanahashi T;Mizuno S
背景资料：非甾体类抗炎药引起严重的小肠溃疡副作用，但关于其对药物代谢和吸收的影响的资料很少。目的：我们研究了吲哚美辛（INM）诱导的SIU大鼠继发性肝脏炎症的存在，并评估了其与细胞色素P450（CYP 450）和P-糖蛋白（mdr 1a），小肠和肝脏中的主要药物代谢因子的关系。方法：采用实时定量聚合酶链反应（qPCR）检测mdr 1a和mdr 1a家族酶的基因表达。万古霉素（VCM），一种吸收不良的药物，经尿道给药SIU大鼠。结果：INM主要在小肠下部区域诱导SIU，并高表达炎性标志物。还观察到肝功能障碍，这表明SIU大鼠中存在继发性炎症反应。在SIUs大鼠的肝脏中，CYP 2C 11、CYP 2 E1和CYP 3A 1的表达显著降低，并且观察到CYP 3A蛋白的丢失。尽管先前的研究表明INM对CYP 3A活性有直接影响，但我们无法证实体外肝脏CY 3A 4（人CYP 3A的主要亚型）表达的任何变化。SIU大鼠血浆VCM浓度升高，是由于粘膜损伤引起的部分吸收，而正常粘膜则无此现象。结论：INM诱导的SIU对肠道炎症表达有微妙的影响，但对肝脏炎症有明显的作用，这至少部分地受到继发性炎症的影响。此外，SIU大鼠的药物吸收增加。
Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.
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影响因子：
2.6
作者：
Hartley, Dylan R.;Dai, Xudong;Evans, David C.
通讯作者：
Evans, David C.
影响因子：
3.9
作者：
Kalitsky-Szirtes, J;Shayeganpour, A;Piquette-Miller, M
通讯作者：
Piquette-Miller, M
DOI：
10.1016/s0304-4165(97)00157-8
发表时间：
1998-05-08
影响因子：
3
作者：
Hiroi, T;Imaoka, S;Funae, Y
通讯作者：
Funae, Y
影响因子：
3.9
作者：
Takara, K;Ohnishi, N;Yokoyama, T
通讯作者：
Yokoyama, T
影响因子：
3.9
作者：
Masubuchi, Yasuhiro;Enoki, Kanako;Horie, Toshiharu
通讯作者：
Horie, Toshiharu