The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans

Our understanding of the fundamental molecular mechanisms of APAP hepatotoxicity began in 1973-1974 when investigators at the US National Institutes of Health published seminal studies demonstrating conversion of APAP to a reactive metabolite that depletes glutathione and binds to proteins in the liver in mice after overdose. Since then, additional groundbreaking experiments have demonstrated critical roles for mitochondrial damage, oxidative stress, nuclear DNA fragmentation, and necrotic cell death too. Over the years, some investigators have also attempted to translate these mechanisms to humans using human specimens from APAP overdose patients. This review presents those studies and summarizes what we have learned about APAP hepatotoxicity in humans so far. Overall, the mechanisms of APAP hepatotoxicity in humans strongly resemble those discovered in experimental mouse and cultured hepatocyte models, while emerging biomarkers also suggest similarities in liver repair. The data not only validate the first mechanistic studies of APAP-induced liver injury performed 50 years ago, but demonstrate the human-relevance of numerous studies conducted since then. Significance Statement Human studies using novel translational, mechanistic biomarkers have confirmed that the fundamental mechanisms of APAP hepatotoxicity discovered in rodent models since 1973 are the same in humans. Importantly, these findings have guided the development and understanding of treatments like N-acetyl-l-cysteine and 4-methylpyrazole over the years. Additional research may improve not only our understanding of APAP overdose pathophysiology in humans but also our ability to predict and treat serious liver injury in patients.