title: An indole derivative protects against acetaminophen-induced liver injury by directly binding to N-acetyl-p-benzoquinone imine in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Kang-Sik
authors.initials: KS
authors.lastname: Seo
authors.forename: Surendar
authors.initials: S
authors.lastname: Tadi
authors.forename: Bong-Hyun
authors.initials: BH
authors.lastname: Ahn
authors.forename: Jung-Uee
authors.initials: JU
authors.lastname: Lee
authors.forename: Jun-Young
authors.initials: JY
authors.lastname: Heo
authors.forename: Jeongsu
authors.initials: J
authors.lastname: Han
authors.forename: Myoung-Sub
authors.initials: MS
authors.lastname: Song
authors.forename: Soon-Ha
authors.initials: SH
authors.lastname: Kim
authors.forename: Yong-Hyeon
authors.initials: YH
authors.lastname: Yim
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: GiRyang
authors.initials: G
authors.lastname: Kweon
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007097:Imines / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D009930:Organic Chemicals / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D007097:Imines; D009930:Organic Chemicals; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C556282:necrox-7; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases; C028473:N-acetyl-4-benzoquinoneimine