A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression
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Oliver Burk
, Katja A. Arnold , Anke Geick , Heike Tegude and Michel Eichelbaum
Abstract
MDR1/P-glycoprotein is an efflux transporter determining the absorption and presystemic elimination of many xenobiotics in the gut. Thus, interindividual differences in MDR1 expression may affect the efficacy of drug treatment. The expression of MDR1 is partially controlled by the pregnane X receptor (PXR), which mediates induction by many xenobiotics. Since it has been described that the nuclear receptors PXR and constitutive androstane receptor (CAR) can bind to the same binding sites, we investigated the role of CAR in the regulation of MDR1 gene expression. We demonstrate here by gel shift and transfection experiments that CAR binds to distinct nuclear receptor response elements in the -7.8 kbp enhancer of MDR1 and transactivates MDR1 expression through DR4 motifs to which the receptor binds as a heterodimer with RXR or as a monomer, respectively. Expression of the endogenous MDR1 gene is elevated in cells stably expressing CAR, thus arguing for the functional relevance of CAR-dependent activation of MDR1. The physiological relevance of the regulation of MDR1 by CAR is further suggested by correlation of the expression of CAR and MDR1 in the human small intestine. In summary, our data suggest that CAR plays a role in the regulation of intestinal MDR1 expression.
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Articles in the same Issue
- A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression
- Molecular structure and transcriptional regulation by nuclear factor-κB of the mouse kinin B1 receptor gene
- The seven E. coli ribosomal RNA operon upstream regulatory regions differ in structure and transcription factor binding efficiencies
- Mapping of B-cell epitopes in E. coli asparaginase II, an enzyme used in leukemia treatment
- Characterisation of human histone H1x
- Biochemical characterization of a cinnamoyl-CoA reductase from wheat
- Kunitz-type Bauhinia bauhinioides inhibitors devoid of disulfide bridges: isolation of the cDNAs, heterologous expression and structural studies
- Assembly of natural and recombinant prion protein into fibrils
- Isolation and structural characterisation of a novel 13-amino acid insulin-releasing peptide from the skin secretion of Agalychnis calcarifer
- Insularinase A, a prothrombin activator from Bothrops insularis venom, is a metalloprotease derived from a gene encoding protease and disintegrin domains
- Evidence for a common regulation in the activation of a polyphenol oxidase by trypsin and sodium dodecyl sulfate