Clock gene mPer2 functions in diurnal variation of acetaminophen induced hepatotoxicity in mice.

The circadian clock gene Period2 (Per2) plays important roles in many physiologic and pathologic processes in mammals. In the previous study, we have reported the protective role of mPer2 against carbon tetrachloride induced hepatotoxicity. Here, we further explore the contribution of this gene to acetaminophen (APAP) induced liver injury in mice. It is reported that the hepatotoxicity induced by APAP exhibited a circadian rhythm in which the peak sensitive injection time is 20:00 while when the administration time becomes to 08:00, it caused markedly decreased liver damage. Thus, we injected APAP into wide type (WT) and mPer2 null mice at the dose of 300 mg/kg at both 08:00 and 20:00. Interestingly, the liver damage showed no significant difference between WT and mPer2 null mice when administered at 08:00, however, liver injury occurred in mPer2 null mice displayed less severe than WT at 20:00. In addition, Cyp1a2, one of the most important cytochrome P450 isoforms responsible for APAP bioactivation, decreased mRNA level at 20:00 in mPer2 null mice while its expression was not different in both strain mice at 08:00. Coincidently, the hepatic circadian rhythm expression of Per2 revealed that its mRNA level was weak at 08:00 but reached peak expression during 24 h at 20:00 in WT mice. Therefore, it is speculated that clock gene mPer2 may function in diurnal variation of APAP induced hepatotoxicity via modulating Cyp1a2 expression in mice.