Abstract: Objective To establish a stable animal model of drug-induced acute hepatic failure (AHF) with different doses of acetaminophen (APAP) by intraperitoneal injection.Methods Sixty mice, which were randomly divided into four groups (n=15), were intraperitoneally injected with saline and different doses of APAP (300 mg/kg, 500 mg/kg and 750 mg/kg), respectively. Mental status, activity and survival rates in different groups were observed within 72 hours. According to the analysis of survival rates, another 180 mice were divided into three groups randomly (n=60) with injection of saline, low (300 mg/kg) and high dose (750 mg/kg) of APAP, respectively. To detect the biochemical and pathological changes of AHF, 12 mice randomly selected from each group were sacrificed for serum and liver tissues collection at 0 h, 1 h, 3 h, 6 h and 12 h after injection, respectively.Results No mice died within 72 h in the control group, APAP (300 mg/kg and 500 mg/kg group) , while the mortality of APAP 750 mg/kg group was 100%. In control group, aminotransferase (ALT) level showed no significant increase at all time points. However, ALT levels in two APAP groups (300 mg/kg and 750 mg/kg) began to increase at 3 h, and reached to peak at 6 h (6766.5±2001.27 IU/L) or 12 h (11707.58±1882.45 IU/L) in low-dose or high-dose APAP group, respectively. Additionally, ALT level in high-dose APAP group was significantly higher than that in low-dose APAP group at 12 h (P<0.01). In view of haematoxylin-eosin (HE) staining, control group displayed normal liver structure. In APAP group, degeneration and necrosis of hepatocytes mainly occurred around central vein, and damage extent gradually expanded over time. In low-dose group, boundaries of necrotic zones were clear with normal liver cell morphology in portal areas, and visible hepatocytes proliferation around the boundaries was observed at 12 h. In high-dose group, typical acute massive hepatic necrosis was found and few of degenerated hepatocytes stayed alive at portal areas. After rapid necrosis of hepatocytes, empty fiber mesh stent remained with large red blood cells deposited in sinusoids and no proliferation of hepatocytes. At 12 h, histological activity index (HAI) score of high-dose group (7.33±1.5) was higher than that of low-dose group (5.25±2.26), which showed statistically significant differences (P<0.05).Conclusion C57BL/6 mice injected with high dose of APAP (750 mg/kg) have similar biochemical and pathological changes with AHF, which might be a reliable AHF model for investigating the role of APAP in pathogenesis and development of liver failure.

Key words: Acetaminophen; Liver failure; Animal model