ToxSci Advance Access originally published online on March 25, 2003
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Toxicological Sciences 73, 386-402 (2003)
Copyright © 2003 by the Society of Toxicology
IN VITRO TOXICOLOGY AND ALTERNATIVE TESTING |
Gene Expression in Two Hepatic Cell Lines, Cultured Primary Hepatocytes, and Liver Slices Compared to the in Vivo Liver Gene Expression in Rats: Possible Implications for Toxicogenomics Use of in Vitro Systems
* F. Hoffmann–La Roche Ltd., Pharmaceuticals Division, Nonclinical Development, CH-4070 Basel, Switzerland;
Basilea Pharmaceutica Ltd., CH-4002 Basel, Switzerland; and
Institute for Pharmacology and Toxicology, University of Jena, Nonnenplan 4, D-07743 Jena, Germany
ABSTRACT
Microarray technology allows the simultaneous analysis of mRNA expression levels of thousands of genes. In the field of toxicogenomics, this technology could help to identify potentially unsafe compounds based on the changes in mRNA expression patterns they induce. Rodent in vivo and in vitro systems are currently the experimental models of choice for predictive toxicology, especially in early phases of development. This study characterizes several hepatic in vitro systems based on mRNA expression profiles, comparing them to gene expression in liver tissue. The in vitro systems investigated comprise two rat liver cell lines (BRL3A and NRL clone 9), primary hepatocytes in conventional monolayer or in sandwich culture, and liver slices. The results demonstrate that liver slices exhibit the strongest similarity to liver tissue regarding mRNA expression, whereas the two cell lines are quite different from the whole liver. We were able to identify genes with strong changes in expression levels in all or at least one of the in vitro systems relative to whole liver. In particular, for some cytochrome P450s the differences observed on the mRNA expression level were paralleled by protein expression and enzymatic activity. In addition, the effect of time in culture was assessed. We were able to show a profound effect of the duration of culture. Expression patterns change most rapidly soon after cell isolation and culture initiation and stabilize with time in culture. The findings are discussed with respect to the usefulness of the various hepatic in vitro systems for microarray-based toxicological testing of compounds.
Key Words: microarray technology; hepatic in vitro system; rat liver cell line; sandwich culture; monolayer; liver slice.
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