Differential gene expression analysis of a known hepatotoxin, N-acetyl-p-amino-phenol (APAP) as compared to its non-toxic analog, N-acetyl-m-amino-phenol (AMAP) in mouse liver

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Drug-induced hepatotoxicity is one of the most common adverse events associated with drug withdrawal from the market. Elucidating the molecular mechanism of hepatotoxicity is essential to predict the safety of a new molecule. To examine genes involved in hepatotoxicity, we have used oligonucleotide CodeLink Bioarrays and determined the transcriptional profile of mice liver treated with hepatotoxic drug N-acetyl-p-amino-phenol (APAP) as well as its non-toxic analog N-acetyl-m-amino-phenol (AMAP). Out of 20,000 genes analyzed, 896 showed differential expression of ≥ 2-fold (648 upregulated and 248 downregulated) within the liver of APAP treated mice as compared to control. In comparison to AMAP treated mice, 62 genes were upregulated and 70 genes were downregulated in mice liver after APAP treatment. Functional classification of these differentially expressed genes identified genes associated with stress response, cell cycle, growth inhibition, cell death, structural components, cell signaling and inflammation. Gene expression profile was further correlated with biochemical analysis and histopathological lesions. These data show that gene expression profiling would help in better understanding the molecular basis of drug-induced hepatotoxicity that will lead to rational development of safer drugs, particularly in pre-clinical stages.
日本トキシコロジー学会の論文
2008-05-01