Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin
Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin
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DOI：
10.1074/jbc.m010173200
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发表时间：
2001-05-04
影响因子：
4.8
通讯作者：
Burk, O
中科院分区：
文献类型：
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作者：
Geick, A;Eichelbaum, M;Burk, O
由MDR1基因编码的肠P-糖蛋白在许多外源物质的吸收和系统前消除中发挥重要作用。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，接触利福平等药物也会严重影响其表达。迄今为止，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 PXR（孕烷 X 受体）参与 CYP3A4 的异生素诱导。由于 CYP3A4 和 MDR1 通常是共同诱导的，因此我们研究了 MDR1 诱导是否也涉及类似的机制。使用人结肠癌细胞系LS174T作为肠道模型来研究诱导，因为在这些细胞中，内源性MDR1基因可被利福平高度诱导。检查人MDR1的5'上游区域是否存在潜在的PXR反应元件。鉴定出几个结合位点，它们在约-8 KB 对处形成复杂的调控簇。该簇中只有一个 DR4 基序是利福平诱导所必需的。我们得出的结论是，MDR1 的诱导是由上游增强子中约 -8 KB 对的 DR4 基序介导的，PXR 与该基序结合。
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.