Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling.
Oxidative stress has been implicated as a mechanism for a variety of forms of liver injury. Although reactive oxygen species (ROS) may damage cellular macromolecules directly, oxidant-induced cell death may result from redox effects on signal transduction pathways. To understand the mechanisms of hepatocyte death from oxidative stress, the functions of the mitogen-activated protein kinases (MAPKs) were determined during oxidant-induced hepatocyte injury from menadione. Low, nontoxic, and high toxic concentrations of the superoxide generator menadione were established in the RALA255-10G rat hepatocyte cell line. Death from menadione was blocked by catalase and ebselen, indicating that death was secondary to oxidant generation and not arylation. Treatment with a nontoxic menadione concentration resulted in a brief activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In contrast, treatment with a toxic menadione concentration induced a prolonged activation of both ERK and JNK. Chemical inhibition of ERK function sensitized RALA hepatocytes to death from previously nontoxic menadione concentrations in association with sustained JNK activation. Adenoviral expression of a dominant-negative protein for c-Jun, a downstream substrate for JNK, blocked death from menadione. The pro-apoptotic effect of c-Jun was not mediated through the mitochondrial death pathway. In conclusion, RALA hepatocyte resistance to oxidant-induced death from menadione is dependent on ERK, whereas cell death is mediated by AP-1 activation. These findings identify signaling pathways that may be therapeutic targets in the prevention or treatment of oxidant-induced liver injury.
Czaja
Mark J
MJ
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. czaja@aecom.yu.edu
Liu
Hailing
H
Wang
Yongjun
Y
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D024483:Vitamin K 3 / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D024483:Vitamin K 3; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases