The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptor-dependent pathway. (January 2019)

• Record Type: Journal Article
• Authors: Knebel, Constanze; Heise, Tanja; Zanger, Ulrich M.; Lampen, Alfonso; Marx-Stoelting, Philip; Braeuning, Albert
• Is Part Of: Food and chemical toxicology. Volume 123(2019)
• Page Start: 481
• Page End: 491
• Publication Date: 2019-01
• Subjects: Pesticides -- Hepatotoxicity -- Nuclear receptors -- Cytochrome P450 -- Xenobiotic metabolism -- Mixtures; AHR aryl hydrocarbon receptor -- CAR constitutive androstane receptor -- CYP cytochrome P450 -- DMSO dimethyl sulfoxide -- DRE dioxin response element -- EROD/MROD 7-ethoxy/methoxyresorufin-O-deethylase -- FCS fetal calf serum -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- PXR pregnane-X-receptor; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.11.039
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Tebuconazole, a member of the triazole group of fungicides, exerts hepatotoxicity in rodent studies. Knowledge on the molecular mechanisms underlying tebuconazole toxicity is limited. Previous studies suggest that activation of xenobiotic-sensing nuclear receptors plays a role in triazole fungicide-mediated hepatotoxicity. This study aimed to characterize the ability of tebuconazole to activate gene expression via the aryl hydrocarbon receptor (AHR). Results demonstrate a statistically significant induction of the AHR target genes CYP1A1 and CYP1A2 in HepG2 and HepaRG human liver cells in vitro at concentrations corresponding to tebuconazole tissue levels reached under subtoxic conditions in vivo . CYP1A1 and CYP1A2 induction was abolished in the presence of an AHR antagonist or in AHR-knockout HepaRG cells, substantiating the importance of the AHR for the observed effects. Although the results indicate that tebuconazole is a weak inducer of AHR-dependent genes, combined exposure of HepaRG cells to tebuconazole and the previously identified AHR agonist propiconazole showed additive effects on CYP1A1 and CYP1A2 expression. In summary, we demonstrate that AHR-downstream gene expression is affected by tebuconazole in an AHR-dependent manner. Data indicate that dose addition may be assumed for the assessment of AHR-related effects of triazole fungicide mixtures. Graphical abstract: Highlights: Tebuconazole activates transcription of AHR-dependent genes in rat liver in vivo . Tebuconazole activates transcription of AHR-dependent genes in human cell lines. Additive effects are observed with tebuconazole/propiconazole mixtures.