Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles

Microarray technology, which allows one to quantitate the expression of tho usands of genes simultaneously, has begun to have a major impact on many di fferent areas of drug discovery and development. The question remains of wh ether microarray analysis and gene expression signature profiles can be app lied to the field of toxicology. To date, there are very few published stud ies showing the use of microarrays in toxicology and important questions re main regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treate d rats with 15 different known hepatotoxins, including allyl alcohol, amiod arone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethyln itrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrile ne, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cau se a variety of hepatocellular injuries including necrosis, DNA damage, cir rhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was do ne on RNA from the livers of treated rats and was compared against vehicle- treated controls. The gene expression results were clustered and compared t o the histopathology findings and clinical chemistry values. Our results sh ow strong correlation between the histopathology, clinical chemistry, and g ene expression profiles induced by the agents. In addition, genes were iden tified whose regulation correlated strongly with effects on clinical chemis try parameters. Overall, the results suggest that microarray assays may pro ve to be a highly sensitive technique for safety screening of drug candidat es and for the classification of environmental toxins. (C) 2001 Academic Pr ess.