title: 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.
abstract: An overdose of acetaminophen (APAP) causes hepatotoxicity due to its metabolite, N-acetyl-p-benzoquinone imine.
  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.
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea.
authors.forename: Jung-Ran
authors.initials: JR
authors.lastname: Noh
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea.
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Chungku, Daejeon, 301-721, South Korea.
authors.forename: Hyo Kyun
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Division of Metrology for Quality Life, Korea Research Institute of Standard and Science (KRISS), Daejeon, South Korea.
authors.forename: Surendar
authors.initials: S
authors.lastname: Tadi
authors.affiliation: Division of Metrology for Quality Life, Korea Research Institute of Standard and Science (KRISS), Daejeon, South Korea.
authors.forename: Yong-Hyeon
authors.initials: YH
authors.lastname: Yim
authors.affiliation: Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Chungku, Daejeon, 301-721, South Korea. minhos@cnu.ac.kr.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea. chullee@kribb.re.kr.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000082:Acetaminophen; D000255:Adenosine Triphosphate; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse
keywords: Acetaminophen; Acute liver injury; Mitochondrial dysfunction; NAD(P)H:quinone oxidoreductase 1