Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice.

Abstract

Acetaminophen (APAP) overdose induces apoptosis-inducing factor (AIF)-dependent necroptosis, but the mechanism remains obscure. The present study investigated the role of receptor interacting protein (RIP)1, a critical mediator of necroptosis, on AIF-dependent necroptosis during APAP-induced acute liver failure. Mice were intraperitoneally injected with APAP (300 mg/kg). As expected, hepatic RIP1 was activated as early as 1 h after APAP, which is earlier than APAP-induced hepatic RIP3 upregulation. APAP-evoked RIP1 activation is associated with hepatic glutathione (GSH) depletion. Either pretreatment or post-treatment with Nec-1, a selective inhibitor of RIP1, significantly alleviated APAP-induced acute liver failure. Moreover, Nec-1 improved the survival and prevented APAP-induced necroptosis, as determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. Further analysis showed that Nec-1 significantly inhibited APAP-induced hepatic c-Jun N-terminal kinase (JNK) phosphorylation and mitochondrial Bax translocation. In addition, Nec-1 blocked APAP-induced translocation of AIF from the mitochondria to the nucleus. Of interest, no changes were induced by Nec-1 on hepatic CYP2E1 expression. In addition, Nec-1 had little effect on APAP-induced hepatic GSH depletion at early stage. Taken together, these results suggest that RIP1 is involved in APAP-induced necroptosis. Nec-1 is an effective antidote for APAP-induced acute liver failure.

• Authors: Ye-Fa Zhang, Wei He, Cheng Zhang, Xiao-Jing Liu, Yan Lu, Hua Wang, Zhi-Hui Zhang, Xi Chen, De-Xiang Xu
• Journal: Toxicology letters (Toxicol Lett) Vol. 225 Issue 3 Pg. 445-53 (Mar 21 2014) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 24440347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apoptosis Inducing Factor
• GTPase-Activating Proteins
• Imidazoles
• Indoles
• Ralbp1 protein, mouse
• necrostatin-1
• Acetaminophen
• Cytochrome P-450 CYP2E1
• JNK Mitogen-Activated Protein Kinases

Topics

• Acetaminophen (administration & dosage, toxicity)
• Animals
• Apoptosis Inducing Factor (metabolism)
• Chemical and Drug Induced Liver Injury (enzymology, etiology, metabolism)
• Cytochrome P-450 CYP2E1 (metabolism)
• GTPase-Activating Proteins (antagonists & inhibitors, metabolism)
• Imidazoles (metabolism)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Indoles (metabolism)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Male
• Mice
• Necrosis (chemically induced, metabolism)