An indole derivative protects against acetaminophen-induced liver injury by directly binding to N-acetyl-p-benzoquinone imine in mice

• Published in: Antioxidants & redox signaling Vol. 18; no. 14; p. 1713
• Main Authors: Park, Ji-Hoon, Seo, Kang-Sik, Tadi, Surendar, Ahn, Bong-Hyun, Lee, Jung-Uee, Heo, Jun-Young, Han, Jeongsu, Song, Myoung-Sub, Kim, Soon-Ha, Yim, Yong-Hyeon, Choi, Hueng-Sik, Shong, Minho, Kweon, GiRyang
• Format: Journal Article
• Language: English
• Published: United States 10-05-2013
• Subjects: Acetaminophen - metabolism; Acetaminophen - toxicity; Animals; Antioxidants - metabolism; Antioxidants - pharmacology; Benzoquinones - metabolism; Cell Death - drug effects; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - prevention & control; Hepatocytes - drug effects; Hepatocytes - metabolism; Imines - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Mice; Organic Chemicals - metabolism; Organic Chemicals - pharmacology; Phosphorylation - drug effects; Reactive Nitrogen Species - metabolism; Reactive Oxygen Species - metabolism
• ISSN: 1557-7716
• DOI: 10.1089/ars.2012.4677

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.
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.
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.
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.