Comparative Analysis of Acute Liver Injury in Mice Following Two Routes of Acetaminophen Administration

Background: Acute liver failure (ALF) is a rare, yet potentially fatal clinical syndrome characterized by the rapid deterioration of hepatic function in individuals without pre-existing liver disease, typically occurring over a period of days to weeks. It is associated with substantial morbidity and mortality, particularly in low-income settings, and is clinically defined by the presence of jaundice, coagulopathy, and hepatic encephalopathy. Among its various etiologies, acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury and ALF, especially in industrialized countries such as the United States and the United Kingdom. In the present study, we compared two experimental approaches for inducing APAP-mediated ALF in mice: oral and intraperitoneal (IP) administration. Methods: While most studies reported in the literature rely on a single route of administration, this comparative analysis provides a more comprehensive evaluation of the advantages and limitations associated with each method, thereby enhancing the reproducibility and translational relevance of experimental ALF models. Results: Our results demonstrate that both administration routes effectively recapitulate key clinical and biochemical features of human ALF, including hepatic encephalopathy, marked elevations in serum transaminases, and high mortality rates. However, the effective APAP dose required to achieve these outcomes differed between the two routes, with 400 mg/kg for IP administration and 500 mg/kg for oral administration, as would be expected based on pharmacokinetic considerations. From a clinical assessment perspective, the use of adapted scoring systems, such as the O’Grady criteria, is essential for evaluating encephalopathy in animal models. Notably, oral administration via gastric gavage requires greater technical expertise, which may influence experimental consistency. Conclusions: Taken together, these findings underscore the importance of route selection in experimental design and highlight the value of comparative approaches for optimizing preclinical models of ALF.