title: Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Svecova
authors.forename: Radim
authors.initials: R
authors.lastname: Vrzal
authors.forename: Ladislav
authors.initials: L
authors.lastname: Burysek
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherova
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.forename: Jiri
authors.initials: J
authors.lastname: Grim
authors.forename: Frantisek
authors.initials: F
authors.lastname: Trejtnar
authors.forename: Jiri
authors.initials: J
authors.lastname: Kunes
authors.forename: Milan
authors.initials: M
authors.lastname: Pour
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Dvorak
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
mesh_terms: D000368:Aged; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin