Document Detail

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:  MEDLINE    
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 a reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), in both humans and rodents. Here, we show that the indole-derived synthetic compound has 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. NecroX-7 could only scavenge NAPQI when hepatocellular GSH levels were very low.
INNOVATION: NecroX-7 is an indole-derived potent antioxidant 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 rodents and humans. Thus, blocking NAPQI formation or eliminating NAPQI are novel strategies for the treatment or prevention of APAP-induced liver injury instead of GSH replenishment.
CONCLUSION: Our data suggest that the 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; Hueng-Sik Choi; Minho Shong; GiRyang Kweon
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-19
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  18     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-05     Completed Date:  2013-10-22     Revised Date:  2014-05-13    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1713-22     Citation Subset:  IM    
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MeSH Terms
Acetaminophen / metabolism,  toxicity*
Antioxidants / metabolism,  pharmacology*
Benzoquinones / metabolism*
Cell Death / drug effects
Drug-Induced Liver Injury / metabolism*,  prevention & control*
Hepatocytes / drug effects,  metabolism
Imines / metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
Organic Chemicals / metabolism,  pharmacology*
Phosphorylation / drug effects
Reactive Nitrogen Species / metabolism
Reactive Oxygen Species / metabolism
Reg. No./Substance:
0/Antioxidants; 0/Benzoquinones; 0/Imines; 0/Organic Chemicals; 0/Reactive Nitrogen Species; 0/Reactive Oxygen Species; 0/necrox-7; 362O9ITL9D/Acetaminophen; EC Mitogen-Activated Protein Kinases; G6S9BN13TI/N-acetyl-4-benzoquinoneimine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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