Fujiyama Nobuhiro, Shitara Yoshihisa, Ito Kousei, Masubuchi Yasuhiro, Horie Toshiharu
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana Chuoku, Chiba 260-8675, Japan.
Biol Pharm Bull. 2007 Mar;30(3):556-61. doi: 10.1248/bpb.30.556.
Previous reports have demonstrated that an intestinal injury causes hypofunctions of the liver associated with down-regulations of cytochrome P450, but an influence on hepatic transporters remains unclear. Here, we tested hepatic transporter functions in a rat model of bowel injury using indomethacin (IDM). After administration of IDM (8.5 mg/kg, i.p., 3 d), the rats suffered the intestinal impairment indicated by a reduction of alkaline phosphatase activity in mucosa. In vivo pharmacokinetic experiments of bromosulfophthalein (BSP) showed that there was a reduction in its plasma elimination rate and cumulative biliary excretion in IDM-treated rats and systemic and biliary clearances reduced to nearly 50% of the control group. Protein expressions in plasma membrane and mRNA levels of organic anion transporting polypeptide 1b2 (Oatp1b2) and multidrug resistance-associated protein 2 (Mrp2), which play hepatic BSP uptake and biliary excretion, respectively, in the liver were significantly reduced following the IDM treatment. In portal plasma, the levels of proinflammatory cytokines were unchanged, while the level of nitric oxide metabolites (NO2- + NO3-) increased to 6.5-fold that of the control. The time-course on IDM treatment indicated that, firstly, intestinal injury was induced, the NO level increased, and the hepatic Oatp1b2 and Mrp2 expression began to fall followed by an increase in plasma ALT. In conclusion, IDM-induced injury to the small intestine causes the hypofunction of hepatic Oatp1b2 and Mrp2 independently on the hepatic impairment, and NO arising from bowel injury may be one of key factors for it through the remote effect.
先前的报告表明，肠道损伤会导致肝脏功能减退，伴有细胞色素P450的下调，但对肝脏转运体的影响仍不清楚。在此，我们使用吲哚美辛（IDM）在大鼠肠道损伤模型中测试了肝脏转运体功能。给予IDM（8.5mg/kg，腹腔注射，3天）后，大鼠出现肠道损伤，表现为黏膜碱性磷酸酶活性降低。溴磺酞钠（BSP）的体内药代动力学实验表明，IDM处理的大鼠其血浆消除率和胆汁累积排泄量降低，全身和胆汁清除率降至对照组的近50%。分别在肝脏中发挥摄取BSP和胆汁排泄作用的质膜蛋白表达以及有机阴离子转运多肽1b2（Oatp1b2）和多药耐药相关蛋白2（Mrp2）的mRNA水平在IDM处理后显著降低。在门静脉血浆中，促炎细胞因子水平未变，而一氧化氮代谢产物（NO2- + NO3-）水平增加至对照组的6.5倍。IDM处理的时间进程表明，首先诱导肠道损伤，NO水平升高，肝脏Oatp1b2和Mrp2表达开始下降，随后血浆ALT升高。总之，IDM诱导的小肠损伤独立于肝脏损伤导致肝脏Oatp1b2和Mrp2功能减退，肠道损伤产生的NO可能是通过远程效应导致此现象的关键因素之一。
