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

In many cases, clinical drug-induced liver injury is poorly predicted by preclinical toxicology studies. To maximise 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 non-rodent 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 non-rodent preclinical species and humans, for adaptation to cellular stress.