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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 2, 2006; DOI: 10.1124/jpet.105.098160

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Received for publication November 9, 2005.
Revised February 28, 2006.
Accepted for publication March 1, 2006.

DIFFERENTIAL REGULATION OF HEPATIC CYP2B6 AND CYP3A4 GENES BY CONSTITUTIVE ANDROSTANE RECEPTOR BUT NOT PREGNANE X RECEPTOR

Stephanie R Faucette 1, Tatsuya Sueyoshi 2, Cornelia M Smith 1, Masahiko Negishi 2, Edward L LeCluyse 3, Hongbing Wang 1*

1 University of North Carolina at Chapel Hill 2 National Institute of Environmental Health Sciences 3 CellzDirect Inc.

* Address correspondence to: E-mail: wang4{at}email.unc.edu

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 implies 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 selectivites of these receptors for CYP2B6 and CYP3A4. Human hepatocyte studies revealed non-selective 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, while 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 containing repeats of CYP2B6 DR4 and CYP3A4 ER6 motifs revealed an even greater difference in reporter activation by hCAR. In contrast, hPXR activation resulted in less discernible differences between CYP2B6 and CYP3A4 reporter gene expression. These results suggest asymmetrical cross-regulation of CYP2B6 and CYP3A4 by hCAR but not hPXR in that hCAR exhibits preferential induction of CYP2B6 relative to CYP3A4 due to its weak binding and functional activation of the CYP3A4 ER6.


Key words: CYP2B6, CYP3A4, Human Constitutive Androstane Receptor, Human Pregnane X Receptor, Human hepatocytes, Regulation


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