Microarray analysis of gene expression has become a powerful approach for exploring the
biological effects of drugs and other chemicals. In toxicology research, gene expression profiling may help identify hazards by comparing results for an experimental compound with a database, and establish mechanistic hypotheses through examination of discrete gene changes. Here we examine the hepatic effects of a
thienopyridine inhibitor of
NF-kappa B-mediated expression of cellular adhesion
proteins. In a 3-day toxicity study in Sprague-Dawley rats,
A-277249 induced
hypertrophy of the liver and elevated serum levels of
alanine aminotransferase (ALT),
aspartate aminotransferase (AST) and
alkaline phosphatase (ALP). To investigate mechanism, microarray analysis was done on
RNA from livers of A-277249-treated rats. Gene expression profiles from
A-277249 were compared with a database of profiles from fifteen known hepatotoxins. Agglomerative hierarchical cluster analysis showed
A-277249 to have a profile most similar to the
aromatic hydrocarbons Aroclor 1254 and
3-methylcholanthrene (3MC), two known activators of the aryl
hydrocarbon nuclear receptor (AhR). Several genes regulated by the AhR, including
cytochrome P450 1A1, were upregulated by
A-277249. In addition, several genes involved in apoptosis and cell cycle were differentially expressed consistent with cell turnover,
hypertrophy and
hyperplasia observed by histology. Results from this study indicate that
A-277249 hepatic toxicity is mediated by the AhR either directly or through effects on
NF-kappa B, and demonstrate the utility of microarray analysis for the rapid identification of toxic hazards for new chemical entities.