Geick A, Eichelbaum M, Burk O
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany.
J Biol Chem. 2001 May 4;276(18):14581-7. doi: 10.1074/jbc.M010173200. Epub 2001 Jan 31.
Intestinal P-glycoprotein, which is encoded by the MDR1 gene, plays an important role in the absorption and presystemic elimination of many xenobiotics. Hence, an understanding of the factors regulating its expression and function is of substantial interest. In addition to genetic factors, exposure to drugs such as rifampin can profoundly affect its expression. So far, the mechanisms by which rifampin induces MDR1 expression are poorly understood. Recent studies demonstrate that the nuclear receptor PXR (pregnane X receptor) is involved in xenobiotic induction of CYP3A4. Because CYP3A4 and MDR1 are often co-induced, we investigated whether a similar mechanism is also involved in MDR1 induction. The human colon carcinoma cell line LS174T was used as an intestinal model to study induction because in these cells the endogenous MDR1 gene is highly inducible by rifampin. The 5'-upstream region of human MDR1 was examined for the presence of potential PXR response elements. Several binding sites were identified that form a complex regulatory cluster at about -8 kilobase pairs. Only one DR4 motif within this cluster is necessary for induction by rifampin. We conclude that induction of MDR1 is mediated by a DR4 motif in the upstream enhancer at about -8 kilobase pairs, to which PXR binds.
由多药耐药基因1（MDR1）编码的肠道P-糖蛋白在许多外源性物质的吸收和首过消除中发挥着重要作用。因此，了解调节其表达和功能的因素具有重要意义。除了遗传因素外，接触利福平等药物会深刻影响其表达。到目前为止，利福平诱导MDR1表达的机制尚不清楚。最近的研究表明，核受体孕烷X受体（PXR）参与外源性物质诱导的CYP3A4表达。由于CYP3A4和MDR1常常共同被诱导，我们研究了类似机制是否也参与MDR1的诱导。人结肠癌细胞系LS174T被用作肠道模型来研究诱导作用，因为在这些细胞中，内源性MDR1基因可被利福平高度诱导。对人MDR1基因的5'上游区域进行检测，以寻找潜在的PXR反应元件。鉴定出了几个结合位点，它们在约-8千碱基对处形成一个复杂的调控簇。该簇中只有一个DR4基序是利福平诱导所必需的。我们得出结论，MDR1的诱导是由位于约-8千碱基对处上游增强子中的一个DR4基序介导的，PXR可与之结合。
