Differential regulation of hepatic CYP2B6 and CYP3A4 genes by constitutive androstane receptor but not pregnane X receptor

The Journal of Pharmacology and Experimental Therapeutics
Stephanie R FaucetteHongbing Wang

Abstract

Accumulated evidence suggests that cross-talk between the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) results in shared transcriptional activation of CYP2B and CYP3A genes. Although most data imply symmetrical cross-regulation of these genes by rodent PXR and CAR, the actual selectivities of the corresponding human receptors are unknown. The objective of this study was to evaluate the symmetry of human (h) PXR and hCAR cross-talk by comparing the selectivities of these receptors for CYP2B6 and CYP3A4. Human hepatocyte studies revealed nonselective induction of both CYP2B6 and CYP3A4 by hPXR activation but marked preferential induction of CYP2B6 by selective hCAR activation. Gel shift assays demonstrated that hPXR exhibited strong and relatively equal binding to all functional response elements in both CYP2B6 and CYP3A4 genes, whereas hCAR displayed significantly weak binding to the CYP3A4 proximal ER6 motif. In cell-based transfection assays, hCAR displayed greater activation of CYP2B6 reporter gene expression compared with CYP3A4 with constructs containing both proximal and distal regulatory elements. Furthermore, in agreement with binding observations, transfection assays using promoter constructs...Continue Reading

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Citations

May 27, 2010·Pharmaceutical Research·Leslie TompkinsHongbing Wang
Sep 11, 2007·Biochemical Pharmacology·Zofia Duniec-DmuchowskiThomas A Kocarek
Oct 24, 2012·The Pharmacogenomics Journal·A HabtewoldE Aklillu
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