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

Cellular stress response pathways such as the nuclear factor erythroid 2-related factor 2 (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. In many cases, clinical drug-induced liver injury is poorly predicted by preclinical toxicology studies. To maximize the translatability of preclinical toxicology studies and inform species selection, we have investigated the relative hepatic stress response capacities of humans and preclinical animal species commonly used in toxicology testing. In control liver tissue, the basal gene and protein expression of stress response pathway components was found to be greater in rodents than nonrodent preclinical species and humans. In addition, following in vitro exposure to pharmacological modulators of autophagy and the NRF2 and ER stress responses, rodent hepatocytes generally displayed a greater capacity, relative to those of nonrodent preclinical species and humans, for adaptation to cellular stress. In all, our results indicate that rodent preclinical species possess a greater basal and adaptive hepatic capacity for mitigation of chemical insult than nonrodent 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, and to interpret the findings of such studies.