Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.
Article Details
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Geick A, Eichelbaum M, Burk O
Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.
J Biol Chem. 2001 May 4;276(18):14581-7. Epub 2001 Jan 31.
- PubMed ID
- 11297522 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Carbamazepine P-glycoprotein 1 Protein Humans UnknownInducerDetails Clotrimazole P-glycoprotein 1 Protein Humans UnknownInhibitorInducerDetails Dexamethasone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Dexamethasone acetate P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Mifepristone P-glycoprotein 1 Protein Humans UnknownInhibitorInducerDetails Reserpine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Rifampicin P-glycoprotein 1 Protein Humans UnknownInducerDetails - Polypeptides
Name UniProt ID Nuclear receptor subfamily 1 group I member 2 O75469 Details