Received for publication August 17, 2007.
Revised November 5, 2007.
Accepted for publication November 7, 2007.

Azole antimycotics differentially affect rifampicin-induced Pregnane X Receptor (PXR)-mediated CYP3A4 gene expression

Abstract

Azole antifungal drug ketoconazole has recently been demonstrated as an inhibitor of a ligand-induced PXR-mediated transcriptional regulation of CYP3A4 gene through disruption of PXR interaction with steroid receptor coactivator-1 (SRC-1). In contrast, other clotrimazole-derived antifungal agents are known as potent inducers of CYP3A4 through PXR. In the present study, we examined effects of azole antimycotics clotrimazole, ketoconazole, econazole, oxiconazole, miconazole, fluconazole and itraconazole on PXR-mediated expression of CYP3A4. We investigated individual effects of the tested azoles as well as their action on rifampicin-induced PXR-mediated transactivation and expression of CYP3A4 in LS174T cell line and primary human hepatocytes, their interactions with PXR ligand-binding domain, and azole-mediated recruitment of SRC-1 to PXR. In addition, applying pharmacodynamic approach and dose-response analysis we aimed to describe the nature of potential interactions of tested azole antimycotics co-administered with a prototypical PXR ligand rifampicin in transactivation of CYP3A4 gene. We describe additive and antagonistic interactions of partial and full agonists of PXR nuclear receptor in the therapeutic group of azole antimycotics in rifampicin-mediated transactivation of CYP3A4. We show that oxiconazole is a highly efficacious activator of CYP3A4 transactivation, which could be antagonized by rifampicin in a competitive manner. In addition, we show that activation of CYP3A4 promoter is a complex process, which is not exclusively determined by azole-PXR interactions and we suggest that ability of some azoles to affect recruitment of SRC-1 to PXR modulates their net effects in transactivation of CYP3A4 both in the absence or presence of rifampicin.

Key words: CYP gene regulation, CYP3A, hepatocytes, nuclear receptors, PXR, SXR, transcriptional regulation