TY  - JOUR
A1  - Luckert, Claudia
A1  - Hessel, Stefanie
A1  - Lenze, Dido
A1  - Lampen, Alfonso
T1  - Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis
JF  - Toxicology in vitro
N2  - 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.
KW  - Pyrrolizidine alkaloids
KW  - Transcriptomics
KW  - Gene expression
KW  - Hepatotoxicity
Y1  - 2015
U6  - https://doi.org/10.1016/j.tiv.2015.06.021
SN  - 0887-2333
VL  - 29
IS  - 7
SP  - 1669
EP  - 1682
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Luckert, Claudia
A1  - Hessel, Stefanie
A1  - Lampen, Alfonso
A1  - Braeuning, Albert
T1  - Utility of an appropriate reporter assay: Heliotrine interferes with GAL4/upstream activation sequence-driven reporter gene systems
JF  - Analytical biochemistry : methods in the biological sciences
N2  - 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.
KW  - Firefly luciferase inhibition
KW  - Nuclear receptor
KW  - Transactivation assay
Y1  - 2015
U6  - https://doi.org/10.1016/j.ab.2015.07.009
SN  - 0003-2697
SN  - 1096-0309
VL  - 487
SP  - 45
EP  - 48
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - CHAP
A1  - Braun, Monique
A1  - Sawada, Stefanie
A1  - Pink, Mario
A1  - Meckert, Christine
A1  - Oberemm, Axel
A1  - Braeuning, Albert
A1  - Lampen, Alfonso
T1  - Proteomic analysis of 3-MCPD and its palmitic ester in rat kidney using a refined tissue extraction method
T2  - NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Y1  - 2015
SN  - 0028-1298
SN  - 1432-1912
VL  - 388
SP  - S88
EP  - S88
PB  - Springer
CY  - New York
ER  -