Identification of Identical Transcript Changes in Liver and Whole Blood during Acetaminophen Toxicity

Liwen Zhang, Pierre R. Bushel, Jeff Chou, Tong Zhou, Paul B. Watkins

The ability to identify mechanisms underlying drug-induced liver injury (DILI) in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a non-invasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG) to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP). In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose) with similar patterns of expression in blood and liver during APAP-induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP-induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only 38 genes were common to both the 6 and 24-h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined.