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首页> 外文期刊>Pharmaceutical research >Microsomal cytochrome P450 levels and activities of isolated rat livers perfused with albumin.
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Microsomal cytochrome P450 levels and activities of isolated rat livers perfused with albumin.

机译：微粒体细胞色素P450水平和灌注白蛋白的离体大鼠肝脏的活性。

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PURPOSE: We recently showed that the perfusion of isolated rat livers with perfusates containing bovine serum albumin (BSA) would significantly stimulate the release of tumor necrosis factor (TNF)-alpha. Here, we hypothesize that BSA-induced increase in the release of TNF-alpha, and possibly other cytokines, would affect cytochrome P450 (CYP)-mediated drug metabolism. METHODS: Rat livers were perfused ex vivo for 1, 2, or 3 h with a physiologic buffer containing or lacking 1% BSA (n = 4-5/group). At the end of perfusion, liver microsomes were prepared and analyzed for their total CYP, CYP2E1, CYP3A2, and CYP2C11 protein contents and the activities of cytochrome c reductase, CYP2E1, CYP3A2, CYP2C11, CYP2E1, CYP2D1, CYP1A1, and CYP2B1/2. In addition, the concentrations of various cytokines and nitric oxide were quantified in the outlet perfusate. RESULTS: In the absence of BSA, the perfusate levels of all measured cytokines and nitric oxide were low. However, when the perfusate contained BSA, the levels of TNF-alpha, interleukin-6, and nitric oxide increased significantly (p < 0.005). Perfusion of the livers for 3 h with the BSA-containing perfusate resulted in significant (p < 0.05) decreases in the total CYP (41%), CYP2E1 (59%), CYP3A2 (68%), and CYP2C11 (50%) protein contents and activities of cytochrome c reductase (31%), CYP2E1 (66%), CYP3A2 (54%), and CYP2G11 (51%). In contrast, perfusion of livers for 1 or 2 h with the BSA perfusate did not have any significant effect on CYP-mediated metabolism. The CYP1A2, CYP2D1, and CYP2B1/2 activities were not affected by BSA, regardless of perfusion time. CONCLUSION: Addition of BSA to perfusates, which is a routine practice in isolated rat liver studies, can reduce CYP-mediated drug metabolism by a mechanism independent of protein-binding effect.
机译：目的：我们最近表明，用含牛血清白蛋白（BSA）的灌注液灌注离体大鼠肝脏会显着刺激肿瘤坏死因子（TNF）-α的释放。在这里，我们假设BSA诱导的TNF-α和其他细胞因子释放的增加会影响细胞色素P450（CYP）介导的药物代谢。方法：用含有或缺乏1％BSA（n = 4-5 /组）的生理缓冲液对大鼠肝脏进行离体灌注1、2或3 h。在灌注结束时，准备肝微粒体并分析其总CYP，CYP2E1，CYP3A2和CYP2C11蛋白含量以及细胞色素c还原酶，CYP2E1，CYP3A2，CYP2C11，CYP2E1，CYP2D1，CYP1A1和CYP1A的活性。另外，在出口灌注液中定量各种细胞因子和一氧化氮的浓度。结果：在没有牛血清白蛋白的情况下，所有测量的细胞因子和一氧化氮的灌注液水平都较低。但是，当灌注液包含BSA时，TNF-α，白介素6和一氧化氮的水平显着增加（p <0.005）。含BSA灌注液的肝脏灌注3小时导致总CYP（41％），CYP2E1（59％），CYP3A2（68％）和CYP2C11（50％）蛋白显着降低（p <0.05）细胞色素c还原酶（31％），CYP2E1（66％），CYP3A2（54％）和CYP2G11（51％）的含量和活性。相反，用BSA灌注液灌注肝脏1或2 h对CYP介导的代谢没有任何显着影响。不论灌注时间如何，BSA均不会影响CYP1A2，CYP2D1和CYP2B1 / 2的活性。结论：在灌肠液中添加牛血清白蛋白（BSA）是一种独立的大鼠肝脏研究的常规方法，它可以通过不依赖蛋白质结合作用的机制来减少CYP介导的药物代谢。

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