High-density microarrays are useful tools to study gene expression for the purpose of characterizing functional tissue changes in response to the action of drugs and chemicals. To test whether high-density expression data can identify mechanisms of toxicity and to identify an unknown sample through its RNA expression pattern, groups of male Wistar rats were administered 6 hepatotoxicants. The compounds chosen for this study were microcystin-LR (MLR), phenobarbital (PB), lipopolysaccharide (LPS), carbon tetrachloride (CT), thioacetamide (THA), and cyproterone acetate (CPA). These hepatotoxicants are known to induce adverse liver effects through different mechanisms. Liver mRNA was isolated and used to generate biotinylated cRNA for hybridization to a custom 1,600 -rat gene DNA microarray. Treatment correlation matrices analyzed hybridization data from a hepatotoxicant-blinded sample, with gene expression coefficients (GEC) evaluated by means of hierarchical cluster analysis and visual representation as dendrograms. The experimental liver toxicity from the different treatments was confirmed by means of concurrent histopathology, liver enzymes, and bilirubin assays. This toxicogenomic analysis identified multiple genes and groups of genes that were affected by the hepatotoxicants on study, indicating that high-density microarray expression data are useful to identify groups of genes involved in toxicity. In addition, the mRNA expression profile of an unidentified sample can be accurately identified when compared with the expression profiles resident in the data set. This study supports the use of gene expression-profiling technology to determine or to predict toxic liver effects. (HEPATOLOGY 2001;33:1239-1258.)Approaches to elucidate cellular mechanisms of injury or function have examined only a small number of genes or proteins at a given time. New technologies are now available that can simultaneously monitor changes in large numbers of cellular macromolecules within a single experiment. High-density DNA microarrays have been assembled to allow the assessment of thousands of genes in a single assay. 1-5 These DNA microarrays are efficient, sensitive, and labor-saving when evaluating RNA expression, and are useful to elucidate cellular pathways and mechanisms involved in inflammatory diseases, tumor suppression, heat shock responses, phorbol ester responses, and cancer. 2,6-9 DNA microarray technology also provides access to the study of abnormal cellular pathways amenable to therapeutic interventions and the discovery of potential drug targets. In addition, DNA microarrays can be used to elucidate mechanisms of xenobiotic-induced toxicity, and hold promise as a tool for predicting toxicologic outcomes of novel drug candidates, thereby conserving drugdevelopment resources and improving the process of risk assessment and safety evaluation. Should changes in RNA expression precede changes in tissue histopathology, comparison of expression profiles from novel compounds with known toxicants in a searchable data set co...

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