Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin*

By A. Geick, M. Eichelbaum, O. Burk. Journal of Biological Chemistry, 2001

896 citations recorded by the source corpus.

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 MDR1are 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 MDR1was 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.

Subfields: Oncology, Pediatrics, Perinatology and Child Health, Pharmacology

View Paper: https://www.semanticscholar.org/paper/59cd0844870087e7debdc990bdeac1776372fcdd

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In Oncology

1. J. Y. Chiang

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Citations in the corpus

• Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. (2002, background): “Both chemicals had marked effects on the expression of GSTA2 (Table 4, line 8) and MDR1 (Table 4, line 9).”
• Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, neutral): “Important targets include members of the xenobiotic-metabolizing phase I CYP enzymes (CYP1A1 and CYP1A2 (Yoshinari et al. 2010), CYP3A4 (Goodwin et al. 2002), CYP2B6 (Sueyoshi et al. 1999), CYP2C9 and CYP2C19 (Gerbal-Chaloin et al. 2002) and CYP2A6 (Itoh et al. 2006)) and enzymes involved in phase I”
• The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. (2002, background): “In the intestine, PXR has been shown to stimulate the expression of MDR1 (84, 94), which encodes an ATP-dependent efflux pump that transports a wide variety of xenobiotics, including many widely used prescription drugs.”
• Induction of phase I, II and III drug metabolism/transport by xenobiotics (2005, background): “A DR4 nuclear receptor response element in the upstream enhancer at about 28 kilobase pairs was identified as a distinct PXR binding site that was essential for MDR1 induction by rifampin (Geick et aL, 2001).”