Ding Yi, Li Qing, Xu Yuan, Chen Yuning, Deng Yue, Zhi Feng, Qian Ke
Department of Geriatrics, Third Affiliated Hospital of Soochow University, Changzhou, China.
Department of Pathology, Third Affiliated Hospital of Soochow University, Changzhou, China.
PLoS One. 2016 May 4;11(5):e0154375. doi: 10.1371/journal.pone.0154375. eCollection 2016.
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. The purpose of this study was to investigate whether paeonol protected against APAP-induced hepatotoxicity. Mice treated with paeonol (25, 50, 100 mg/kg) received 400 mg/kg acetaminophen intraperitoneally (i.p.) and hepatotoxicity was assessed. Pre-treatment with paeonol for 6 and 24 h ameliorated APAP-induced hepatic necrosis and significantly reduced the serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels in a dose-dependent manner. Post-treatment with 100 mg/kg paeonol ameliorated APAP-induced hepatic necrosis and reduced AST and ALT levels in the serum after APAP administration for 24 h. Western blot revealed that paeonol inhibited APAP-induced phosphorylated JNK protein expression but not p38 and Erk1/2. Moreover, paeonol showed anti-oxidant activities with reducing hepatic MDA contents and increasing hepatic SOD, GSH-PX and GSH levels. Paeonol dose-dependently prevented against H2O2 or APAP-induced LDH releasing and ROS production in primary mouse hepatocytes. In addition, the mRNA levels of pro-inflammatory genes such as TNF-α, MCP-1, IL-1β and IL-6 in the liver were dose-dependently reduced by paeonol pre-treatment. Pre-treatment with paeonol significantly inhibited IKKα/β, IκBα and p65 phosphorylation which contributed to ameliorating APAP-induced hepatic inflammation. Collectively, the present study demonstrates paeonol has a protective ability against APAP-induced hepatotoxicity and might be an effective candidate compound against drug-induced acute liver failure.
对乙酰氨基酚（APAP）过量是药物性急性肝衰竭最常见的原因。本研究的目的是调查丹皮酚是否能预防APAP诱导的肝毒性。用丹皮酚（25、50、100mg/kg）处理的小鼠腹腔注射（i.p.）400mg/kg对乙酰氨基酚，并评估肝毒性。丹皮酚预处理6小时和24小时可改善APAP诱导的肝坏死，并以剂量依赖性方式显著降低血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平。100mg/kg丹皮酚在APAP给药24小时后进行后处理，可改善APAP诱导的肝坏死并降低血清中的AST和ALT水平。蛋白质印迹法显示，丹皮酚可抑制APAP诱导的磷酸化JNK蛋白表达，但不影响p38和Erk1/2。此外，丹皮酚具有抗氧化活性，可降低肝脏MDA含量，提高肝脏SOD、GSH-PX和GSH水平。丹皮酚在原代小鼠肝细胞中剂量依赖性地预防H2O2或APAP诱导的LDH释放和ROS产生。此外，丹皮酚预处理可剂量依赖性地降低肝脏中促炎基因如TNF-α、MCP-1、IL-1β和IL-6的mRNA水平。丹皮酚预处理显著抑制IKKα/β、IκBα和p65磷酸化，这有助于改善APAP诱导的肝脏炎症。总的来说，本研究表明丹皮酚对APAP诱导的肝毒性具有保护作用，可能是对抗药物性急性肝衰竭的有效候选化合物。
