Rifampin induces the intestinal MDR1 gene through nuclear receptor response elements. The study shows that the MDR1 gene is highly inducible by rifampin in the human colon carcinoma cell line LS174T. The induction occurs through a DR4 motif located at about -8 kilobase pairs in the upstream regulatory region of the MDR1 gene. This motif is bound by the nuclear receptor PXR (pregnane X receptor), which is involved in the induction of CYP3A4. The study also demonstrates that PXR binds to a cluster of nuclear response elements in the MDR1 promoter, including three DR4 motifs and one DR3 and ER6 motif. Reporter gene assays confirmed that the DR4 motif is essential for rifampin-induced MDR1 expression. Additionally, PXR/RXRα heterodimers specifically bind to the DR4 and ER6/DR4 motifs. The results indicate that PXR is the endogenous factor responsible for rifampin-induced MDR1 expression in LS174T cells. The study provides evidence that PXR-mediated induction is involved in the co-induction of CYP3A4 and MDR1. The findings suggest that PXR plays a key role in the regulation of MDR1 expression in the intestine, which is important for the absorption and presystemic elimination of xenobiotics. The study also highlights the importance of understanding the molecular mechanisms underlying drug-induced changes in MDR1 expression, as this has implications for drug metabolism and toxicity.Rifampin induces the intestinal MDR1 gene through nuclear receptor response elements. The study shows that the MDR1 gene is highly inducible by rifampin in the human colon carcinoma cell line LS174T. The induction occurs through a DR4 motif located at about -8 kilobase pairs in the upstream regulatory region of the MDR1 gene. This motif is bound by the nuclear receptor PXR (pregnane X receptor), which is involved in the induction of CYP3A4. The study also demonstrates that PXR binds to a cluster of nuclear response elements in the MDR1 promoter, including three DR4 motifs and one DR3 and ER6 motif. Reporter gene assays confirmed that the DR4 motif is essential for rifampin-induced MDR1 expression. Additionally, PXR/RXRα heterodimers specifically bind to the DR4 and ER6/DR4 motifs. The results indicate that PXR is the endogenous factor responsible for rifampin-induced MDR1 expression in LS174T cells. The study provides evidence that PXR-mediated induction is involved in the co-induction of CYP3A4 and MDR1. The findings suggest that PXR plays a key role in the regulation of MDR1 expression in the intestine, which is important for the absorption and presystemic elimination of xenobiotics. The study also highlights the importance of understanding the molecular mechanisms underlying drug-induced changes in MDR1 expression, as this has implications for drug metabolism and toxicity.