Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression.

Article Details

Citation

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
DrugTargetKindOrganismPharmacological ActionActions
ClotrimazoleNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details
EconazoleNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Partial agonist
Details
KetoconazoleNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Antagonist
Details
MiconazoleNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Partial agonist
Details
OxiconazoleNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Partial agonist
Details
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
OxiconazoleCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
Pharmaco-transcriptomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
ClotrimazoleApproved Vet ApprovedCYP3A41576
upregulated
Clotrimazole results in increased expression of CYP3A4 mRNA7q22.1
ClotrimazoleApproved Vet ApprovedNR1I28856
upregulated
Clotrimazole results in increased expression of NR1I2 mRNA3q13.33
EconazoleApprovedCYP3A41576
upregulated
Econazole results in increased expression of CYP3A4 mRNA7q22.1
ItraconazoleApproved InvestigationalNR1I28856
upregulated
Itraconazole results in increased expression of NR1I2 mRNA3q13.33
KetoconazoleApproved InvestigationalCYP3A41576
upregulated
Ketoconazole results in increased expression of CYP3A4 mRNA7q22.1
KetoconazoleApproved InvestigationalNR1I28856
downregulated
Ketoconazole results in decreased expression of NR1I2 mRNA3q13.33
MiconazoleApproved Investigational Vet ApprovedCYP3A41576
upregulated
Miconazole results in increased expression of CYP3A4 mRNA7q22.1
MiconazoleApproved Investigational Vet ApprovedNR1I28856
downregulated
Miconazole results in decreased expression of NR1I2 mRNA3q13.33
OxiconazoleApprovedCYP3A41576
upregulated
oxiconazole results in increased expression of CYP3A4 mRNA7q22.1
OxiconazoleApprovedNR1I28856
downregulated
oxiconazole results in decreased expression of NR1I2 mRNA3q13.33
RifampicinApprovedCYP3A41576
upregulated
Rifampin results in increased expression of CYP3A4 mRNA7q22.1