Abstract
Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide.
However, due to its wide availability, it is frequently implicated in intentional
or unintentional overdoses where it can cause severe liver injury and even acute liver
failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the
United States. Early mechanistic studies in mice demonstrated the formation of a reactive
metabolite, which is responsible for hepatic glutathione depletion and initiation
of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as
a clinical antidote. However, more recently, substantial progress was made in further
elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein
adducts trigger a mitochondrial oxidant stress, which requires amplification through
a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK)
in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced
oxidant stress is responsible for the membrane permeability transition pore opening
and the membrane potential breakdown. The ensuing matrix swelling causes the release
of intermembrane proteins such as endonuclease G, which translocate to the nucleus
and induce DNA fragmentation. These pathophysiological signaling mechanisms can be
additionally modulated by removing damaged mitochondria by autophagy and replacing
them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed
in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose
patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory
response. Although recruitment of inflammatory cells is necessary for removal of cell
debris in preparation for regeneration, these cells have the potential to aggravate
the injury. This review touches on the newest insight into the intracellular mechanisms
of APAP-induced cells death and the resulting inflammatory response. Furthermore,
it discusses the translation of these findings to humans and the emergence of new
therapeutic interventions.
Keywords
drug-induced liver injury - apoptosis - necroptosis - mitochondrial dysfunction -
DNA fragmentation - sterile inflammation
