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ToxSci Advance Access published online on May 22, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm131
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Acute hepatotoxicity: A predictive model based on focussed Illumina microarrays

Nadine Zidek*, Juergen Hellmann{dagger}, Peter-Juergen Kramer{ddagger} and Philip G. Hewitt*,§

* Molecular Toxicology {dagger} Pathology and Histopathology {ddagger} Institute of Toxicology, Merck KGaA, Darmstadt, 64293 Germany

§ corresponding author: Philip G. Hewitt, Institute of Toxicology - Molecular Toxicology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany. TEL: +49-6151-722927, FAX: +49-6151-912927 philip.hewitt{at}merck.de

Received February 28, 2007; revision received May 14, 2007; accepted May 14, 2007


  Abstract

Drug-induced hepatotoxicity is a major issue for drug development, and toxicogenomics has the potential to predict toxicity during early toxicity screening. A bead-based Illumina oligonucleotide microarray containing 550 liver specific genes has been developed. We have established a predictive screening system for acute hepatotoxicity by analyzing differential gene expression profiles of well-known hepatotoxic and non-hepatotoxic compounds. Low and high doses of tetracycline, carbon tetrachloride, 1-naphthylisothiocyanate, erythromycin estolate, acetaminophen or chloroform as hepatotoxicants, clofibrate, theophylline, naloxone, estradiol, quinidine or dexamethasone as non-hepatotoxic compounds, were administered as a single dose to male Sprague Dawley rats. After 6h, 24h and 72h, livers were taken for histopathological evaluation and for analysis of gene expression alterations. All hepatotoxic compounds tested generated individual gene expression profiles. Based on leave-one-out cross-validation analysis, gene expression profiling allowed the accurate discrimination of all model compounds, 24h after high dose treatment. Even during the regeneration phase, 72h after treatment, carbon tetrachloride, 1-naphthylisothiocyanate and acetaminophen were predicted to be hepatotoxic, and only these three compounds showed histopathological changes at this time. Furthermore, we identified 64 potential marker genes responsible for class prediction, which reflected typical hepatotoxicity responses. These genes and pathways, commonly deregulated by hepatotoxicants, may be indicative of the early characterization of hepatotoxicity and possibly predictive of later hepatotoxicity onset. Two unknown test compounds were used for pre-validating the screening test system, with both being correctly predicted. We conclude that focussed gene microarrays are sufficient to classify compounds with respect to toxicity prediction.

Key Words: gene expression changes; toxicogenomics; early prediction; screening model; Illumina microarray; rat in vivo model.


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