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In order to minimise the occurrence of unexpected toxicities as a new medicine transitions from the preclinical to clinical phases of development, it is vital to understand fundamental similarities and differences between preclinical species and humans. The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically-based pharmacokinetic modelling to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Despite pharmacokinetic and biochemical verification of the equivalent NAPQI insult, serum biomarker and tissue histopathology analyses revealed that mice still exhibited a greater degree of liver injury than rats. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats, indicative of a more robust transcriptional adaptation to the equivalent insult. Using RNA-Seq data, we also found that genes associated with these stress responses are expressed at a higher basal level in the livers of rats compared with both mice and humans. Taken together, these data indicate that rats possess a greater basal and adaptive capacity for hepatic stress responses than mice and humans. This has important implications for species selection in preclinical safety testing of drugs associated with reactive metabolite formation and other forms of chemical stress.

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