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Gene Expression Profiles in Rat Liver Slices Exposed to Hepatocarcinogenic Enzyme Inducers, Peroxisome Proliferators, and 17-Ethinylestradiol

German Cancer Research Center, (DKFZ), Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany

Marie Charlotte von Brevern
Julia Scheel

Axaron Biosience AG, Heidelberg, Germany

Thorsten Storck

Gentana GmbH, Heidelberg, Germany

Dieter Müller
Reinhild Glöckner

Institute of Pharmacology and Toxicology, Friedrich-Schiller-University, Jena, Germany

Helmut Bartsch
Matthias Bartelmann

German Cancer Research Center, (DKFZ), Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany

Correspondence: Address correspondence to Gisela Werle-Schneider, German Cancer Research Center (DKFZ), Division of Toxicology and Cancer Risk Factors, 69120 Heidelberg, Im Neuenheimer Feld 280, Germany. E-mail:g.werle{at}dkfz.de

Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, -hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer^TM DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.

Key Words: In Vitro Assay • Microarray • Rat Liver Slices • Toxicogenomics • Tumor Promoters

International Journal of Toxicology, Vol. 25, No. 5, 379-395 (2006)
DOI: 10.1080/10915810600846963


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