title: Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis.
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 μM 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 |fold change| 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, NFκB 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 PPARα/γ/δ 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.
authors.affiliation: Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Luckert
authors.affiliation: Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany. Electronic address: stefanie.hessel@bfr.bund.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hessel
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.affiliation: Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lampen
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D015894:Genome, Human; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D011763:Pyrrolizidine Alkaloids; D012333:RNA, Messenger
keywords: Gene expression; Hepatotoxicity; Pyrrolizidine alkaloids; Transcriptomics