PMID- 38187538
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
DP  - 2023 Dec 23
TI  - Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in 
      mice.
LID - 2023.12.21.572856 [pii]
LID - 10.1101/2023.12.21.572856 [doi]
AB  - 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 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 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 APAP mediated activation of RAGE 
      and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a 
      cofactor of Glo-1, psi-GSH, were employed as tools. Our findings show elevated 
      oxidative stress, 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 is the appearance of microvesicular 
      steatosis as a result of centrilobular necrosis, rather than inflammation seen in 
      wild type. The GSH surrogate and general antioxidant, psi-GSH alleviated APAP 
      toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the 
      primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in 
      GKO mice suggests the importance of this enzyme system in antioxidant defense 
      against initial stages of APAP overdose.
FAU - Dobariya, Prakashkumar
AU  - Dobariya P
AD  - Center for Drug Design, College of Pharmacy, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
FAU - Xie, Wei
AU  - Xie W
AD  - Center for Drug Design, College of Pharmacy, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
FAU - Rao, Swetha Pavani
AU  - Rao SP
AD  - Center for Drug Design, College of Pharmacy, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
FAU - Xie, Jiashu
AU  - Xie J
AD  - Center for Drug Design, College of Pharmacy, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
FAU - Seelig, Davis M
AU  - Seelig DM
AD  - Comparative Pathology Shared Resource, Masonic Cancer Center, University of 
      Minnesota, St. Paul, Minnesota 55108, USA.
AD  - College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 
      55108, USA.
FAU - Vince, Robert
AU  - Vince R
AD  - Center for Drug Design, College of Pharmacy, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
FAU - Lee, Michael K
AU  - Lee MK
AD  - Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 
      55455, USA.
AD  - Institute for Translational Neuroscience, University of Minnesota, Minneapolis, 
      Minnesota 55455, USA.
FAU - More, Swati S
AU  - More SS
AD  - Center for Drug Design, College of Pharmacy, University of Minnesota, 
      Minneapolis, Minnesota 55455, USA.
LA  - eng
GR  - R01 AG062469/AG/NIA NIH HHS/United States
PT  - Preprint
DEP - 20231223
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10769331
OTO - NOTNLM
OT  - acetaminophen
OT  - advanced glycation end product
OT  - antidote
OT  - glyoxalase 1
OT  - hepatotoxicity
OT  - methylglyoxal
OT  - psi-glutathione
COIS- Conflicts of Interest: S.S.M. and R.V. are co-inventors on the patent 
      applications relating to psi-GSH and its analogs as treatment options of 
      neurodegenerative disorders and liver diseases. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2024/01/08 06:42
MHDA- 2024/01/08 06:43
PMCR- 2024/01/05
CRDT- 2024/01/08 04:46
PHST- 2024/01/08 06:42 [pubmed]
PHST- 2024/01/08 06:43 [medline]
PHST- 2024/01/08 04:46 [entrez]
PHST- 2024/01/05 00:00 [pmc-release]
AID - 2023.12.21.572856 [pii]
AID - 10.1101/2023.12.21.572856 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Dec 23:2023.12.21.572856. doi: 
      10.1101/2023.12.21.572856.