Host: The Japanese Society of Toxicology
Overdose when APAP is metabolized by CYP2E1, which consequently increases the reactive Acetaminophen (APAP)-induced liver injury (AILI) occurs as a consequence of APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI). APAP overdose can cause a serious acute liver injury and acute hepatic failure that can result in need for liver transplantation or death. Although AILI is also reported to be immune related, the detail is unclear. In this study, the mechanism of AILI pathogenesis was evaluated in vivo and in vitro study. In AILI model rats (800 mg/kg, ip), the levels of AST and ALT levels were increased only at 12-24 h. Caspase (C)-3 and C-9 levels rose at 6-9 h, whereas C-8 level rose hours later, moreover, 24 h after; C-3/-8/-9 levels re-rose. In human hepatocyte cells, cytochrome c was released from the mitochondria which is promoted by oxidative stress due to drug metabolism (APAP 1.0 mM) and C-9 was activated. Thus, mitochondrial damage might be caused by NAPQI as early reaction. In the next stage, inflammasomes of human antigen presenting cells were activated by damage-associated molecular patterns (DAMPs), which were released from damaged hepatocyte caused by APAP (0.3 mM). It is confirmed that AILI is included in immune related adverse event, thereby, in case of N-acetylcysteine refractory, it is suggested that steroid hormones administration should be effective and recommended as a novel strategy for AILI with immune related adverse events.
