Jihong Lu1, Hu Wang1, Rumeng Zhang1, Zhikang Wan1, Hang Gao1, Jie Cai1, Yujia Cheng1, Dong Pu1, Tengfei Lin1, Chenyu Fan1, Ying Sun2. 1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. 2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. sunyingwyo@163.com.
Abstract
PURPOSE: Acetaminophen (APAP) is a clinically popular analgesic and antipyretic drug, but excessive APAP can cause fatal hepatotoxicity. Many factors affect the degree of APAP-induced liver injury. This study aimed to investigate how circadian rhythm affects the development of APAP-induced hepatotoxicity and to clarify the roles of photoperiod and dietary rhythm on APAP-induced hepatotoxicity in mice. METHODS: APAP-induced hepatotoxicity models were established by intraperitoneal injection of APAP (400 mg/kg) to mice. The mice were then divided into three treatment groups: normal diet, reversed diet, and reversed photoperiod. RESULTS: More severe liver injury was observed at zeitgeber time 12 (ZT12) than at zeitgeber time 0 (ZT0) in all treatment groups, suggesting that photoperiod played a critical role in APAP-induced liver injury. We observed a change in the expression of the circadian gene Per2, which may be responsible for regulation of liver injury by photoperiod. Our results showed negligible change in Per2 expression with diet reversion, whereas Cry1, Cry2, and Dbp expressions were more highly affected by diet reversion than was Per2 expression. Downstream effects including liver enzyme expression, GSH level, and inflammation factors were also examined to identify the mechanism of liver injury. The results indicated that the circadian gene Per2 participated in APAP biometabolism by regulating the expression of Cyp2e1, which may explain the more severe hepatotoxicity at ZT12 than at ZT0. CONCLUSION: APAP-induced hepatotoxicity can be mediated by photoperiod through the circadian gene Per2, suggesting that medicines containing APAP should be administered not only with food but also according to the appropriate photoperiod.
PURPOSE:Acetaminophen (APAP) is a clinically popular analgesic and antipyretic drug, but excessive APAP can cause fatal hepatotoxicity. Many factors affect the degree of APAP-induced liver injury. This study aimed to investigate how circadian rhythm affects the development of APAP-induced hepatotoxicity and to clarify the roles of photoperiod and dietary rhythm on APAP-induced hepatotoxicity in mice. METHODS:APAP-induced hepatotoxicity models were established by intraperitoneal injection of APAP (400 mg/kg) to mice. The mice were then divided into three treatment groups: normal diet, reversed diet, and reversed photoperiod. RESULTS: More severe liver injury was observed at zeitgeber time 12 (ZT12) than at zeitgeber time 0 (ZT0) in all treatment groups, suggesting that photoperiod played a critical role in APAP-induced liver injury. We observed a change in the expression of the circadian gene Per2, which may be responsible for regulation of liver injury by photoperiod. Our results showed negligible change in Per2 expression with diet reversion, whereas Cry1, Cry2, and Dbp expressions were more highly affected by diet reversion than was Per2 expression. Downstream effects including liver enzyme expression, GSH level, and inflammation factors were also examined to identify the mechanism of liver injury. The results indicated that the circadian gene Per2 participated in APAP biometabolism by regulating the expression of Cyp2e1, which may explain the more severe hepatotoxicity at ZT12 than at ZT0. CONCLUSION:APAP-induced hepatotoxicity can be mediated by photoperiod through the circadian gene Per2, suggesting that medicines containing APAP should be administered not only with food but also according to the appropriate photoperiod.
Authors: A O Taranov; A N Puchkova; P A Slominsky; T V Tupitsyna; V V Dementiyenko; V B Dorokhov Journal: Zh Nevrol Psikhiatr Im S S Korsakova Date: 2017