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Deletion of Glyoxalase 1 Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.
Dobariya, Prakashkumar; Xie, Wei; Rao, Swetha Pavani; Xie, Jiashu; Seelig, Davis M; Vince, Robert; Lee, Michael K; More, Swati S.
Afiliación
  • Dobariya P; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Xie W; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Rao SP; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Xie J; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Seelig DM; Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, St. Paul, MN 55108, USA.
  • Vince R; College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
  • Lee MK; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • More SS; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Antioxidants (Basel) ; 13(6)2024 May 25.
Article en En | MEDLINE | ID: mdl-38929087
ABSTRACT
Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Antioxidants (Basel) Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Antioxidants (Basel) Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza