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ToxSci Advance Access originally published online on June 27, 2003
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Toxicological Sciences 75, 208-222 (2003)
Copyright © 2003 by the Society of Toxicology

SYSTEMS TOXICOLOGY

Assessment of Hepatocytes and Liver Slices as in Vitro Test Systems to Predict in Vivo Gene Expression

Bart A. Jessen*,1,2, Jennifer S. Mullins{dagger},1, Ann de Peyster{dagger} and Gregory J. Stevens*

* Pfizer Global Research and Development, 10724 Science Center Drive, La Jolla, California, 92121, and {dagger} Graduate School of Public Health, San Diego State University, San Diego, California 92182

The use of in vitro systems to predict in vivo responses to chemical agents provides the benefits of requiring fewer animals, reducing variability between samples, requiring less test material, and enabling higher throughput. In the present study rat tissue slices and primary hepatocytes were compared as in vitro systems to predict in vivo changes in gene expression in response to treatment with known liver toxicants or inducers. Five compounds (phenobarbital, carbon tetrachloride, Wy-14,634, alpha-napthylisothiocyanate, and tacrine) were chosen for their established and diverse mechanisms of hepatoxicity or microsomal induction. Expression profiles from male Sprague-Dawley rats or in vitro systems treated for 24 h were measured by DNA oligonucleotide microarrays containing 8700 probe sets. Qualitative comparison of expression revealed a >80% concordance between in vivo liver and both in vitro systems; however, the responsiveness of both in vitro systems to compound-induced changes in gene expression was far less than that of in vivo. Furthermore, both in vitro systems appeared similar in their ability to reproduce compound-induced changes in gene expression observed in vivo.

Key Words: microarray; hepatocytes; liver slices; hepatotoxicity; gene expression.


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