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An indole-derivative protects against acetaminophen-induced liver injury by directly binding to N-acetyl-p-benzoquinone imine in mice.
MedLine Citation:
PMID:  23121402     Owner:  NLM     Status:  Publisher    
Aims: Acetaminophen (APAP)-induced liver injury is mainly due to the excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) through the formation of reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI) in both human and rodent. Here, we show that the indole-derived synthetic compound have a protective effect against APAP-induced liver injury in C57Bl/6 mice model. Results: NecroX-7 decreased tert-butylhydroperoxide (t-BHP)- and APAP-induced cell death and ROS/RNS formation in HepG2 human hepatocarcinoma and primary mouse hepatocytes. In mice, NecroX-7 decreased APAP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and 3-nitrotyrosine (3-NT) formation, and also protected mice from APAP-induced liver injury and lethality by binding directly to NAPQI. The binding of NecroX-7 to NAPQI did not require any of cofactors or proteins. And NecroX-7 could only scavenge NAPQI when hepatocellular GSH levels were very low. Innovation: NecroX-7 is an indole-derived potent anti-oxidant molecule, which can be bound to some types of radicals and especially NAPQI. It is well known that the NAPQI is a major intermediate of APAP, which causes necrosis of hepatocytes in rodent and human. Thus, blocking NAPQI formation or eliminating NAPQI are novel strategy for the treatment or prevention of APAP-induced liver injury instead of GSH replenishment. Conclusion: Our data suggest that indole-derivative, NecroX-7, directly binds to NAPQI when hepatic GSH levels are very low and the NAPQI-NecroX-7 complex is secreted to the blood from the liver. NecroX-7 shows more preventive and similar therapeutic effects against APAP-induced liver injury when compared to the effect of N-acetylcysteine in C57Bl/6 mice.
Ji-Hoon Park; Kang-Sik Seo; Surendar Tadi; Bong-Hyun Ahn; Jung-Uee Lee; Jun-Young Heo; Jeongsu Han; Myoung-Sub Song; Soon-Ha Kim; Yong-Hyeon Yim; H-S Choi; Minho Shong; Gi Ryang Kweon
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-2
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  -     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
School of Medicine, Chungnam National University, Department of Biochemistry, Daejeon, Korea, Republic of;
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