Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression.
Article Details
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Svecova L, Vrzal R, Burysek L, Anzenbacherova E, Cerveny L, Grim J, Trejtnar F, Kunes J, Pour M, Staud F, Anzenbacher P, Dvorak Z, Pavek P
Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression.
Drug Metab Dispos. 2008 Feb;36(2):339-48. Epub 2007 Nov 12.
- PubMed ID
- 17998298 [ View in PubMed]
- Abstract
Azole antifungal drug ketoconazole has recently been demonstrated as an inhibitor of a ligand-induced pregnane X receptor (PXR)-mediated transcriptional regulation of the CYP3A4 gene through disruption of PXR interaction with steroid receptor coactivator (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 the pharmacodynamic approach and dose-response analysis, we aimed to describe the nature of potential interactions of tested azole antimycotics coadministered 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 the CYP3A4 promoter is a complex process, which is not exclusively determined by azole-PXR interactions, and we suggest that the 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Clotrimazole Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownActivatorDetails Econazole Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownPartial agonistDetails Ketoconazole Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownAntagonistDetails Miconazole Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownPartial agonistDetails Oxiconazole Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownPartial agonistDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Oxiconazole Cytochrome P450 3A4 Protein Humans UnknownInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Clotrimazole Approved Vet Approved CYP3A4 1576 upregulated Clotrimazole results in increased expression of CYP3A4 mRNA 7q22.1 Clotrimazole Approved Vet Approved NR1I2 8856 upregulated Clotrimazole results in increased expression of NR1I2 mRNA 3q13.33 Econazole Approved CYP3A4 1576 upregulated Econazole results in increased expression of CYP3A4 mRNA 7q22.1 Itraconazole Approved Investigational NR1I2 8856 upregulated Itraconazole results in increased expression of NR1I2 mRNA 3q13.33 Ketoconazole Approved Investigational CYP3A4 1576 upregulated Ketoconazole results in increased expression of CYP3A4 mRNA 7q22.1 Ketoconazole Approved Investigational NR1I2 8856 downregulated Ketoconazole results in decreased expression of NR1I2 mRNA 3q13.33 Miconazole Approved Investigational Vet Approved CYP3A4 1576 upregulated Miconazole results in increased expression of CYP3A4 mRNA 7q22.1 Miconazole Approved Investigational Vet Approved NR1I2 8856 downregulated Miconazole results in decreased expression of NR1I2 mRNA 3q13.33 Oxiconazole Approved CYP3A4 1576 upregulated oxiconazole results in increased expression of CYP3A4 mRNA 7q22.1 Oxiconazole Approved NR1I2 8856 downregulated oxiconazole results in decreased expression of NR1I2 mRNA 3q13.33 Rifampicin Approved CYP3A4 1576 upregulated Rifampin results in increased expression of CYP3A4 mRNA 7q22.1