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

Abstract

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.

• Authors: 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
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 18 Issue 14 Pg. 1713-22 (May 10 2013) ISSN: 1557-7716 [Electronic] United States
• PMID: 23121402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Benzoquinones
• Imines
• Organic Chemicals
• Reactive Nitrogen Species
• Reactive Oxygen Species
• necrox-7
• Acetaminophen
• JNK Mitogen-Activated Protein Kinases
• N-acetyl-4-benzoquinoneimine

Topics

• Acetaminophen (metabolism, toxicity)
• Animals
• Antioxidants (metabolism, pharmacology)
• Benzoquinones (metabolism)
• Cell Death (drug effects)
• Chemical and Drug Induced Liver Injury (metabolism, prevention & control)
• Hepatocytes (drug effects, metabolism)
• Imines (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Mice
• Organic Chemicals (metabolism, pharmacology)
• Phosphorylation (drug effects)
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)