期刊
TOXICOLOGY LETTERS
卷 225, 期 3, 页码 445-453出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2014.01.005
关键词
Acetaminophen; Necroptosis; Receptor-interacting protein (RIP) kinases; Apoptosis-inducing factor (AIF); Necrostatin-1 (Nec-1)
类别
资金
- National Natural Science Foundation of China [81373495, 30371667, 30572223, 30973544, 81001480]
- Natural Science Foundation of Anhui province [090413142, 1308085MH120]
- Department of Education of Anhui in China [KJ2011A159]
- University Excellence Young Talent Fund of Educational Commission of Anhui Province [2011SQRL058]
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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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