Microarray analysis of hepatotoxins in vitro reveals a correlation betweengene expression profiles and mechanisms of toxicity

A rate-limiting step that occurs in the drug discovery process is toxicolog ical evaluation of new compounds. New techniques that use small amounts of the experimental compound and provide a high degree of predictivity would g reatly improve this process. The field of microarray technology, which allo ws one to monitor thousands of gene expression changes simultaneously, is r apidly advancing and is already being applied to numerous areas in toxicolo gy. However, it remains to be determined if compounds with similar toxic me chanisms produce similar changes in transcriptional expression. In addition , it must be determined if gene expression changes caused by an agent in vi tro would reflect those produced in vivo. In order to address these questio ns, we treated rat hepatocytes with 15 known hepatoxins (carbon tetrachlori de, allyl alcohol, aroclor 1254, methotrexate, diquat, carbamazepine, metha pyrilene, arsenic, diethylnitrosamine, monocrotaline, dimethyl-formamide, a miodarone, indomethacin, etoposide, and 3-methylcholanthrene) and used micr oarray technology to characterize the compounds based on gene expression ch anges. Our results showed that gene expressional profiles for compounds wit h similar toxic mechanisms indeed formed clusters, suggesting a similar eff ect on transcription. There was not complete identity, however, indicating that each compound produced a unique signature. These results show that lar ge-scale analysis of gene expression using microarray technology has promis e as a diagnostic tool for toxicology. (C) 2001 Elsevier Science Ireland Lt d. All rights reserved.