TY  - JOUR
A1  - Knebel, Constanze
A1  - Neeb, Jannika
A1  - Zahn, Elisabeth
A1  - Schmidt, Flavia
A1  - Carazo, Alejandro
A1  - Holas, Ondej
A1  - Pavek, Petr
A1  - Püschel, Gerhard Paul
A1  - Zanger, Ulrich M.
A1  - Süssmuth, Roderich
A1  - Lampen, Alfonso
A1  - Marx-Stoelting, Philip
A1  - Braeuning, Albert
T1  - Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells
JF  - Toxicological sciences
N2  - 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.
KW  - triazole fungicides
KW  - constitutive androstane receptor
KW  - pregnane X-receptor
KW  - enzyme induction
KW  - liver toxicity
KW  - mixtures
Y1  - 2018
U6  - https://doi.org/10.1093/toxsci/kfy026
SN  - 1096-6080
SN  - 1096-0929
VL  - 163
IS  - 1
SP  - 170
EP  - 181
PB  - Oxford Univ. Press
CY  - Oxford
ER  -