Acetaminophen-induced hepatocyte injury: C2-ceramide and oltipraz intervention, hepatocyte nuclear factor 1 and glutathione S-transferase A1 changes.

Abstract

Acetaminophen (APAP) is an antipyretic and analgesic, which is commonly associated with drug-induced hepatic injury. C2-ceramide plays a key role in mediating cell life activities, and oltipraz was extensively studied as a cancer chemopreventive agent. Glutathione S-transferase A1 (GSTA1) acts as a vital liver detoxification enzyme. Hepatocyte nuclear factor 1 (HNF-1) regulates various cellular signaling pathways. In this study, we investigated the effects of C2-ceramide and oltipraz on APAP-induced hepatocyte injury and the changes of HNF-1 and GSTA1. Results showed that C2-ceramide (6μmol/L) exacerbated APAP-induced hepatocyte injury and caused a significant decrease (P<.01) in HNF-1 and GSTA1 expressions. Meanwhile, GSTA1 content in supernatant was significantly increased (P<.01). In contrast, oltipraz (8μmol/L) reduced the injury and significantly elevated (P<.01) HNF-1 and GSTA1 expressions while GSTA1 content in supernatant was significantly decreased (P<.01). In conclusion, these findings revealed that C2-ceramide inhibited HNF-1 and GSTA1 expression and exacerbated hepatocyte injury, while oltipraz treatment results in the reduction of hepatocyte injury, and promoted HNF-1 and GSTA1 expression. Additionally, the changes in HNF-1 and GSTA1 were related to APAP-induced hepatocyte injury. These results were useful to investigate the mechanism of an antipyretic and analgesic drug combination.