Diabetic KK-A(y) mice are highly susceptible to oxidative hepatocellular damage induced by acetaminophen

作者：Kon Kazuyoshi; Ikejima Kenichi^*; Okumura Kyoko; Arai Kumiko; Aoyama Tomonori; Watanabe Sumio

来源：American Journal of Physiology - Gastrointestinal and Liver Physiology, 2010, 299(2): G329-G337.

DOI：10.1152/ajpgi.00361.2009

• drug-induced liver injury
• metabolic syndrome
• steatohepatitis
• oxidative stress
• hepatotoxicity

Kon K, Ikejima K, Okumura K, Arai K, Aoyama T, Watanabe S. Diabetic KK-A(y) mice are highly susceptible to oxidative hepatocellular damage induced by acetaminophen. Am J Physiol Gastrointest Liver Physiol 299: G329-G337, 2010. First published June 10, 2010; doi:10.1152/ajpgi.00361.2009.-Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-A(y) mice, an animal model of metabolic syndrome. Twelve-week-old male KK-A(y) and C57Bl/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-non-enal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun NH2-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichloro-dihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-A(y) mice than in C57Bl/6 mice and significantly increased serum alanine aminotransferase levels in KK-A(y) mice. Acetaminophen induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-Ay mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-Ay mice. Exposure to 20 mu M tert-butyl hydroperoxide did not kill hepatocytes isolated from C57Bl/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-A(y) mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-Ay mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury.

• 出版日期2010-8