Universität zu Köln

Grinberg, Marianna, Stoeber, Regina M., Albrecht, Wiebke, Edlund, Karolina, Schug, Markus, Godoy, Patricio, Cadenas, Cristina ORCID: 0000-0003-3374-6418, Marchan, Rosemarie, Lampen, Alfonso, Braeuning, Albert, Buhrke, Thorsten, Leist, Marcel ORCID: 0000-0002-3778-8693, Oberemm, Axel, Hellwig, Birte, Kamp, Hennicke, Gardner, Iain, Escher, Sylvia, Taboureau, Olivier, Aguayo-Orozco, Alejandro, Sachinidis, Agapios, Ellinger-Ziegelbauer, Heidrun, Rahnenfuehrer, Joerg and Hengstler, Jan G. (2018). Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes. Arch. Toxicol., 92 (12). S. 3517 - 3534. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Grinberg, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoeber, Regina M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Albrecht, Wiebke UNSPECIFIED UNSPECIFIED UNSPECIFIED Edlund, Karolina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schug, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Godoy, Patricio UNSPECIFIED UNSPECIFIED UNSPECIFIED Cadenas, Cristina UNSPECIFIED orcid.org/0000-0003-3374-6418 UNSPECIFIED Marchan, Rosemarie UNSPECIFIED UNSPECIFIED UNSPECIFIED Lampen, Alfonso UNSPECIFIED UNSPECIFIED UNSPECIFIED Braeuning, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Buhrke, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED Oberemm, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hellwig, Birte UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamp, Hennicke UNSPECIFIED UNSPECIFIED UNSPECIFIED Gardner, Iain UNSPECIFIED UNSPECIFIED UNSPECIFIED Escher, Sylvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Taboureau, Olivier UNSPECIFIED UNSPECIFIED UNSPECIFIED Aguayo-Orozco, Alejandro UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Ellinger-Ziegelbauer, Heidrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuehrer, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-163480
DOI:	10.1007/s00204-018-2352-3
Journal or Publication Title:	Arch. Toxicol.
Volume:	92
Number:	12
Page Range:	S. 3517 - 3534
Date:	2018
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE-EXPRESSION ALTERATIONS; LIVER; VITRO; DIFFERENTIATION; SENSITIVITY; SYSTEMS; DESIGN; CELLS Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16348