Cell culture model for acetaminophen-induced hepatocyte death in vivo

摘要: Overdose of the popular, and relatively safe, analgesic acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol) can produce a fatal centrilobular liver injury. APAP-induced cell death was investigated in differentiated, transforming growth factor alpha (TGFalpha)-overexpressing, hepatocyte line found to occur at concentrations, over time frames, relevant clinical overdose situations. Coordinated multiorganellar collapse evident during cytotoxicity with widespread, yet selective, protein degradation events vitro. Cellular proteasomal activity inhibited APAP treatment but not comparatively nonhepatotoxic regioisomer, N-acetyl-m-aminophenol (AMAP). Low concentrations proteasome-directed inhibitor MG132 (N-carbobenzoxyl-Leu-Leu-Leucinal) increased chromatin condensation cellular stress responses preferentially AMAP-treated cultures, suggesting contribution proteasome APAP- AMAP-mediated death. APAP-specific alterations mitochondria were observed morphologically evidence mitochondrial proliferation Biochemical proteolytic also vivo, including or inhibition caspase-3 processing. These results indicate that, although retaining some attributes apoptosis, both have additional distinctive features consistent longer term necrosis.