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Toxicol Sci. 2018 May 1;163(1):170-181. doi: 10.1093/toxsci/kfy026.

Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells.

Author information

1
Department of Food Safety.
2
Department of Pesticides Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany.
3
Department of Pharmacology and Toxicology.
4
Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University, Hradec Kralove 500 05, Czech Republic.
5
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany.
6
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, and Eberhard-Karls-University, Tuebingen, Germany.
7
Institute of Chemistry, Technical University Berlin, 10623 Berlin, Germany.
8
Department of Experimental Toxicology and ZEBET, German Federal Institute for Risk Assessment, 12277 Berlin, Germany.

Abstract

Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group and are therefore thought to display similar and additive behavior. Our data show that Te is an antagonist of the constitutive androstane receptor (CAR) in rats and humans, while propiconazole is an agonist of this receptor. Both substances activate the pregnane X-receptor (PXR) and further induce mRNA expression of CYP3A4. CYP3A4 enzyme activity, however, is inhibited by propiconazole. For common targets of PXR and CAR, the activation of PXR by Te overrides CAR inhibition. In summary, propiconazole and Te affect different hepatotoxicity-relevant cellular targets and, depending on the individual endpoint analyzed, act via similar or dissimilar mechanisms. The use of molecular data based on research in human cell systems extends the picture to refine cumulative assessment group grouping and substantially contributes to the understanding of mixture effects of chemicals in biological systems.

PMID:
29420809
DOI:
10.1093/toxsci/kfy026
[Indexed for MEDLINE]

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