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Papers In Press, published online ahead of print January 31, 2001
J. Biol. Chem, 10.1074/jbc.M010173200
Submitted on November 8, 2000
Revised on January 24, 2001
Accepted on January 31, 2001

Nuclear response elements mediate induction of intestinal MDR1 by rifampin

Anke Geick, Michel Eichelbaum, and Oliver Burk

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376, Stuttgart

Corresponding Author: oliver.burk{at}ikp-stuttgart.de

Intestinal P-glycoprotein which is encoded by the MDR11 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 demonstrated that the nuclear receptor PXR 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, which form a complex regulatory cluster at about - 8kb. 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 - 8kb, to which PXR binds.


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