Hepatic cellular stress response pathways exhibit species differences in basal and inducible activity

Cellular stress response pathways such as the NRF2 oxidative stress response, endoplasmic reticulum (ER) stress response and macroautophagy afford protection against many forms of drug toxicity, including the liver toxicity associated with the formation of reactive drug metabolites. To maximise the translatability of preclinical toxicology studies, an understanding of the relative hepatic stress response capacities of humans and widely-used preclinical animal species is vital. In control liver tissue, the basal gene and protein expression of stress response pathway components was found to be greater in rodents than non-rodent preclinical species and humans. In addition, following in vitro exposure to pharmacological modulators of the NRF2 and ER stress responses, rodent hepatocytes generally displayed a greater capacity, relative to those of non-rodent preclinical species and humans, for adaptation to cellular stress. Consistent with the reported lower concordance of drug toxicity between humans and rats, the latter displayed a greater level of Torin1-induced autophagic flux than all other species, while the robust transcriptional responses to thapsigargin-induced endoplasmic reticulum stress and Bardoxolone- or Ki696-mediated NRF2 activation were comparable between mouse and rat hepatocytes. In all, our results indicate that rodent preclinical species possess a greater basal and adaptive hepatic capacity for mitigation of chemical insult than non- rodent preclinical species and humans. This study represents the first to provide a comprehensive comparison of stress response pathway capacity of humans and the animal species most commonly used for preclinical drug safety assessment. Our findings can be used to inform the selection of species for safety testing of drugs with a liability for reactive metabolite-mediated liver toxicity.