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Originally published In Press as doi:10.1074/jbc.M010173200 on January 31, 2001

J. Biol. Chem., Vol. 276, Issue 18, 14581-14587, May 4, 2001
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Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin*

Anke GeickDagger , Michel EichelbaumDagger §, and Oliver BurkDagger

From the Dagger  Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany and § Division of Clinical Pharmacology, Eberhard-Karls University, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany

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.

* This work was supported by Deutsche Forschungsgemeinschaft (Germany) Grant Bu 1249/1-1 and by the Robert Bosch Foundation (Germany).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel: 49 (0)711/8101-3753; Fax: 49 (0)711/859295; E-mail: oliver.burk@ikp-stuttgart.de.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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