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Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes.

Affiliation
Department of Statistics, TU Dortmund University, Dortmund, Germany.
Grinberg, Marianna;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Stöber, Regina M.;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Albrecht, Wiebke;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Edlund, Karolina;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Schug, Markus;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Godoy, Patricio;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Cadenas, Cristina;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Marchan, Rosemarie;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Lampen, Alfonso;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Braeuning, Albert;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Buhrke, Thorsten;
Affiliation
Fachbereich Biologie, University of Konstanz, Universitätsstrasse 1, 78457, Konstanz, Germany.
Leist, Marcel;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Oberemm, Axel;
ORCID
0000-0003-2806-7250
Affiliation
Department of Statistics, TU Dortmund University, Dortmund, Germany.
Hellwig, Birte;
Affiliation
BASF SE, Experimental Toxicology and Ecology, Ludwigshafen am Rhein, Germany.
Kamp, Hennicke;
Affiliation
Simcyp (A Certara Company), Sheffield, UK.
Gardner, Iain;
Affiliation
Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
Escher, Sylvia;
Affiliation
Center for Protein Research, Novo Nordisk Foundation Center for Protein Research (NNFCPR), University of Copenhagen (UCPH), Copenhagen, Denmark.
Taboureau, Olivier;
Affiliation
Center for Protein Research, Novo Nordisk Foundation Center for Protein Research (NNFCPR), University of Copenhagen (UCPH), Copenhagen, Denmark.
Aguayo-Orozco, Alejandro;
Affiliation
Institute of Neurophysiology and Centre for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
Sachinidis, Agapios;
Affiliation
Investigational Toxicology, Drug Discovery, Pharmaceuticals, Bayer AG, 42096, Wuppertal, Germany.
Ellinger-Ziegelbauer, Heidrun;
Affiliation
Department of Statistics, TU Dortmund University, Dortmund, Germany.
Rahnenführer, Jörg;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany. hengstler@ifado.de.
Hengstler, Jan G.

Transcriptomics is developing into an invaluable tool in toxicology. The aim of this study was, using a transcriptomics approach, to identify genes that respond similar to many different chemicals (including drugs and industrial compounds) in both rat liver in vivo and in cultivated hepatocytes. For this purpose, we analyzed Affymetrix microarray expression data from 162 compounds that were previously tested in a concentration-dependent manner in rat livers in vivo and in rat hepatocytes cultivated in sandwich culture. These data were obtained from the Japanese Toxicogenomics Project (TGP) and North Rhine-Westphalian (NRW) data sets, which represent 138 and 29 compounds, respectively, and have only 5 compounds in common between them. The in vitro gene expression data from the NRW data set were generated in the present study, while TGP is publicly available. For each of the data sets, the overlap between up- or down-regulated genes in vitro and in vivo was identified, and named in vitro-in vivo consensus genes. Interestingly, the in vivo-in vitro consensus genes overlapped to a remarkable extent between both data sets, and were 21-times (upregulated genes) or 12-times (down-regulated genes) enriched compared to random expectation. Finally, the genes in the TGP and NRW overlap were used to identify the upregulated genes with the highest compound coverage, resulting in a seven-gene set of Cyp1a1, Ugt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3, and Ehhadh. This seven-gene set was then successfully tested with structural analogues of valproic acid that are not present in the TGP and NRW data sets. In conclusion, the seven-gene set identified in the present study responds similarly in vitro and in vivo to a wide range of different chemicals. Despite these promising results with the seven-gene set, transcriptomics with cultivated rat hepatocytes remains a challenge, because in general many genes are up- or downregulated by in vitro culture per se, respond differently to test compounds in vitro and in vivo, and/or show higher variability in the in vitro system compared to the corresponding in vivo data.

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