| An indole-derivative protects against acetaminophen-induced liver injury by directly binding to N-acetyl-p-benzoquinone imine in mice. | |
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MedLine Citation:
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PMID: 23121402 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-11-2 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: - ISSN: 1557-7716 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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School of Medicine, Chungnam National University, Department of Biochemistry, Daejeon, Korea, Republic of; alwaysmile@cnu.ac.kr. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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