Down-regulation of hepatic cytochrome P450 enzymes in rats with trinitrobenzene sulfonic acid-induced colitis
Down-regulation of hepatic cytochrome P450 enzymes in rats with trinitrobenzene sulfonic acid-induced colitis
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DOI：
10.1124/dmd.107.018754
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Horie, Toshiharu
中科院分区：
文献类型：
--
作者：
Masubuchi, Yasuhiro;Enoki, Kanako;Horie, Toshiharu
肝脏细胞色素P450（P450）酶在炎症过程中下调。在这项研究中，炎症性肠病的动物模型进行表征肝脏P450表达的炎症条件下。用溶于30%乙醇的100 mg/kg三硝基苯磺酸（TNBS）对大鼠进行结肠内给药，并制备大鼠结肠粘膜和肝微粒体的匀浆。结肠炎伴有门静脉内毒素、白细胞介素-6和一氧化氮代谢产物水平升高，以及肝脏CYP 3A 2、CYP 2C 11的含量和活性降低，以及较小程度的CYP 1A 2和CYP 2 E1降低。尼美舒利，一个优先的考克斯-2抑制剂，保护大鼠与TNBS诱导的结肠炎（TNBS结肠炎）对下调肝脏CYP 3A 2。多粘菌素B（可中和内毒素）、姜黄素（具有抗炎特性）和氯化钆（可灭活巨噬细胞）可减弱CYP 3A 2的下调。在其他P450如CYP 2C 11中也观察到类似的作用，但这些药物在减弱下调方面效果较差。我们的数据表明，内源性物质泄漏从受损的结肠与TNBS结肠炎大鼠激活枯否细胞，导致下调肝脏P450的差异敏感性的炎症刺激。该模型可代替外源性脂多糖或细胞因子，用于研究轻度炎症条件下肝脏P450表达及其他肝功能改变的机制。
Hepatic cytochrome P450 (P450) enzymes are down-regulated during inflammation. In this study, an animal model of inflammatory bowel disease was subjected to characterization of hepatic P450 expression under inflammatory conditions. Rats were treated intracolonically with 100 mg/kg trinitrobenzene sulfonic acid (TNBS) dissolved in 30% ethanol, and homogenates of colonic mucosa and hepatic microsomes of the rats were prepared. The colitis was accompanied by appearance of higher levels of portal endotoxin, interleukin-6, and nitric oxide metabolites and decreases in contents and activities for hepatic CYP3A2, CYP2C11, and, to a lesser extent, CYP1A2 and CYP2E1. Nimesulide, a preferential COX-2 inhibitor, protected rats with TNBS-induced colitis (TNBS-colitis) against the down-regulation of hepatic CYP3A2. Polymyxin B, which neutralizes endotoxin, curcumin, which has anti-inflammatory properties, and gadolinium chloride, which inactivates macrophages, attenuated the down-regulation of CYP3A2. Similar effects were observed in other P450s such as CYP2C11, but the agents were less effective in attenuating the down-regulation. Our data suggest that endogenous substances leaked from damaged colon in the rats with TNBS-colitis activate Kupffer cells, leading to down-regulation of hepatic P450s with differential susceptibility to the inflammatory stimuli. The colitis model, instead of exogenous administration of lipopolysaccharide or cytokines, could be applied to the study on mechanisms for altered hepatic P450 expression and other liver functions under mild inflammatory conditions.