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Archives of Toxicology

, Volume 89, Issue 11, pp 2159–2166 | Cite as

The protective role of NAD(P)H:quinone oxidoreductase 1 on acetaminophen-induced liver injury is associated with prevention of adenosine triphosphate depletion and improvement of mitochondrial dysfunction

  • Jung Hwan Hwang
  • Yong-Hoon Kim
  • Jung-Ran Noh
  • Gil-Tae Gang
  • Kyoung-Shim Kim
  • Hyo Kyun Chung
  • Surendar Tadi
  • Yong-Hyeon Yim
  • Minho Shong
  • Chul-Ho Lee
Short communication

Abstract

An overdose of acetaminophen (APAP) causes hepatotoxicity due to its metabolite, N-acetyl-p-benzoquinone imine. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important enzyme for detoxification, because it catabolizes endogenous/exogenous quinone to hydroquinone. Although various studies have suggested the possible involvement of NQO1 in APAP-induced hepatotoxicity, its precise role in this remains unclear. We investigated the role of NQO1 against APAP-induced hepatotoxicity using a genetically modified rodent model. NQO1 wild-type (WT) and knockout (KO) mice were treated with different doses of APAP, and we evaluated the mortality and toxicity markers for cell death caused by APAP. NQO1 KO mice showed high sensitivity to APAP-mediated hepatotoxicity (as indicated by a large necrotic region) as well as increased levels of nitrotyrosine adducts and reactive oxygen species. APAP-induced cell death in the livers and primary hepatocytes of NQO1 KO mice, which was accompanied by an extensive reduction in adenosine triphosphate (ATP) levels. In accordance with this ATP depletion, cytosolic increases in mitochondrial proteins such as apoptosis-inducing factor, second mitochondria-derived activator of caspases/DIABLO, endonuclease G, and cytochrome c, which indicate severe mitochondrial dysfunction, were observed in NQO1 KO mice but not in WT mice after APAP exposure. Severe mitochondrial depolarization was also greater in hepatocytes isolated from NQO1 KO mice. Collectively, our data suggest that NQO1 plays a critical role in protection against energy depletion caused by APAP, and NQO1 may be useful in the development of therapeutic approaches to effectively diminish the hepatotoxicity caused by an APAP overdose.

Keywords

NAD(P)H:quinone oxidoreductase 1 Acetaminophen Acute liver injury Mitochondrial dysfunction 

Abbreviations

NQO1

NAD(P)H:quinone oxidoreductase

APAP

Acetaminophen

NAPQI

N-acetyl-p-benzoquinone imine

ROS

Reactive oxygen species

GSH

Glutathione

MPT

Mitochondrial permeability transition

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

AIF

Apoptosis-inducing factor

Endo G

Endonuclease G

RNS

Reactive nitrogen species

JNK

c-Jun N-terminal kinase

ETC

Electron transport chain

PCNA

Proliferating cell nuclear antigen

ESI

Electrospray ionization

Notes

Acknowledgments

This work was supported by the KRIBB Research Initiative Program of Korea and a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (H10C0573), and a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2013R1A2A1A01011071). The authors thank Dong-Hee Choi for technical assistance.

Conflict of interest

The authors declare that there are no conflict of interest.

Supplementary material

204_2014_1340_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jung Hwan Hwang
    • 1
  • Yong-Hoon Kim
    • 1
  • Jung-Ran Noh
    • 1
  • Gil-Tae Gang
    • 1
  • Kyoung-Shim Kim
    • 1
  • Hyo Kyun Chung
    • 2
  • Surendar Tadi
    • 3
  • Yong-Hyeon Yim
    • 3
  • Minho Shong
    • 2
  • Chul-Ho Lee
    • 1
  1. 1.Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)University of Science and TechnologyDaejeonSouth Korea
  2. 2.Department of Internal Medicine, Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonSouth Korea
  3. 3.Division of Metrology for Quality LifeKorea Research Institute of Standard and Science (KRISS)DaejeonSouth Korea

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