@article{KnebelNeebZahnetal.2018,
  author    = {Knebel, Constanze and Neeb, Jannika and Zahn, Elisabeth and Schmidt, Flavia and Carazo, Alejandro and Holas, Ondej and Pavek, Petr and P{\"u}schel, Gerhard Paul and Zanger, Ulrich M. and S{\"u}ssmuth, Roderich and Lampen, Alfonso and Marx-Stoelting, Philip and Braeuning, Albert},
  title     = {Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells},
  series = {Toxicological sciences},
  volume    = {163},
  journal   = {Toxicological sciences},
  number    = {1},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1096-6080},
  doi       = {10.1093/toxsci/kfy026},
  pages     = {170 -- 181},
  year      = {2018},
  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.},
  language  = {en}
}
@inproceedings{BraunSawadaPinketal.2015,
  author    = {Braun, Monique and Sawada, Stefanie and Pink, Mario and Meckert, Christine and Oberemm, Axel and Braeuning, Albert and Lampen, Alfonso},
  title     = {Proteomic analysis of 3-MCPD and its palmitic ester in rat kidney using a refined tissue extraction method},
  series = {NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY},
  volume    = {388},
  booktitle = {NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY},
  publisher = {Springer},
  address   = {New York},
  issn      = {0028-1298},
  pages     = {S88 -- S88},
  year      = {2015},
  language  = {en}
}
@article{LuckertHesselLenzeetal.2015,
  author    = {Luckert, Claudia and Hessel, Stefanie and Lenze, Dido and Lampen, Alfonso},
  title     = {Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis},
  series = {Toxicology in vitro},
  volume    = {29},
  journal   = {Toxicology in vitro},
  number    = {7},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0887-2333},
  doi       = {10.1016/j.tiv.2015.06.021},
  pages     = {1669 -- 1682},
  year      = {2015},
  abstract  = {1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 mu M of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a vertical bar fold change vertical bar of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NF kappa B and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPAR alpha/gamma/delta were predicted to be inhibited. In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure. (C) 2015 Elsevier Ltd. All rights reserved.},
  language  = {en}
}
@article{LuckertHesselLampenetal.2015,
  author    = {Luckert, Claudia and Hessel, Stefanie and Lampen, Alfonso and Braeuning, Albert},
  title     = {Utility of an appropriate reporter assay: Heliotrine interferes with GAL4/upstream activation sequence-driven reporter gene systems},
  series = {Analytical biochemistry : methods in the biological sciences},
  volume    = {487},
  journal   = {Analytical biochemistry : methods in the biological sciences},
  publisher = {Elsevier},
  address   = {San Diego},
  issn      = {0003-2697},
  doi       = {10.1016/j.ab.2015.07.009},
  pages     = {45 -- 48},
  year      = {2015},
  abstract  = {Reporter gene assays are widely used for the assessment of transcription factor activation following xenobiotic exposure of cells. A critical issue with such assays is the possibility of interference of test compounds with the test system, for example, by direct inhibition of the reporter enzyme. Here we show that the pyrrolizidine alkaloid heliotrine interferes with reporter signals derived from GAL4-based nuclear receptor transactivation assays by a mechanism independent of luciferase enzyme inhibition. These data highlight the necessity to conduct proper control experiments in order to avoid perturbation of reporter assays by test chemicals. (C) 2015 Elsevier Inc. All rights reserved.},
  language  = {en}
}