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

Toxicology Letters
J F WaringR G Ulrich

Abstract

A rate-limiting step that occurs in the drug discovery process is toxicological evaluation of new compounds. New techniques that use small amounts of the experimental compound and provide a high degree of predictivity would greatly improve this process. The field of microarray technology, which allows one to monitor thousands of gene expression changes simultaneously, is rapidly advancing and is already being applied to numerous areas in toxicology. However, it remains to be determined if compounds with similar toxic mechanisms produce similar changes in transcriptional expression. In addition, it must be determined if gene expression changes caused by an agent in vitro would reflect those produced in vivo. In order to address these questions, we treated rat hepatocytes with 15 known hepatoxins (carbon tetrachloride, allyl alcohol, aroclor 1254, methotrexate, diquat, carbamazepine, methapyrilene, arsenic, diethylnitrosamine, monocrotaline, dimethyl-formamide, amiodarone, indomethacin, etoposide, and 3-methylcholanthrene) and used microarray technology to characterize the compounds based on gene expression changes. Our results showed that gene expressional profiles for compounds with similar toxic mechanisms indeed formed cluste...Continue Reading

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