Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells.
Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells.
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发表时间：
1996-02
影响因子：
3.6
通讯作者：
E. Schuetz;W. T. Beck;J. Schuetz
中科院分区：
文献类型：
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作者：
E. Schuetz;W. T. Beck;J. Schuetz
外源生物经常诱导与其解毒有关的蛋白质。由于许多由人细胞色素P450(CYP)3A4和3A5代谢的药物也是通过药物外排泵P-糖蛋白转运的，我们确定了不同药物是否改变了这些蛋白在人结肠腺癌LS180/WT及其阿霉素耐药亚系LS180/AD50中的表达。P-糖蛋白和CYP3A4在LS180/AD50和LS180/WT细胞中均有结构性表达，经利福平、苯巴比妥、克霉唑、利血平和异黄樟素等药物处理后，P-糖蛋白和细胞色素P3A4表达上调。然而，也有一些例外，因为咪达唑仑和硝苯地平上调P-糖蛋白，而CYP3A4不上调。在这些细胞中也有结构性表达的CYP3A5，在大多数药物治疗中保持不变，但被利血平和克霉唑上调。细胞色素P3A基因家族与P-糖蛋白在LS180细胞中的协同共表达表明，对于常见的口服药物，P-糖蛋白可能在药物净吸收和共享底物的药物/药物相互作用中发挥重要作用。
Xenobiotics frequently induce proteins involved in their detoxification. Because many drugs that are metabolized by human cytochromes P450 (CYP) 3A4 and 3A5 are also transported by the drug efflux pump P-glycoprotein, we determined whether expression of these proteins was altered by a variety of drugs in a cell line derived from a human colon adenocarcinoma, LS180/WT, and its adriamycin-resistant subline, LS180/AD50. P-glycoprotein and CYP3A4 were constitutively expressed in both LS180/AD50 and LS180/WT cells, and both proteins were up-regulated after treatment with many drugs, including rifampicin, phenobarbital, clotrimazole, reserpine, and isosafrole. However, there were some exceptions because P-glycoprotein was up-regulated by midazolam and nifedipine, whereas CYP3A4 was not. CYP3A5, which is also constitutively expressed in these cells, remained unchanged with most drug treatments but was up-regulated by reserpine and clotrimazole. The apparent coordinated coexpression of the CYP3A gene family and P-glycoprotein in the LS180 cells suggests that for common orally administered drugs, P-glycoprotein may play an important role in net drug absorption and drug/drug interactions of shared CYP3A4/P-glycoprotein substrates.