Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346-Insensitive Nuclear Translocation of GAPDH

PLoS One. 2016 Aug 11;11(8):e0160982. doi: 10.1371/journal.pone.0160982. eCollection 2016.

Abstract

The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals during cellular stress via several post-translational modifications that change its folding properties, protein-protein interactions and sub-cellular localization. We examined GAPDH properties in acute mouse liver injury due to ethanol and/or acetaminophen (APAP) treatment. Synergistic robust and time-dependent nuclear accumulation and aggregation of GAPDH were observed only in combined, but not individual, ethanol/APAP treatments. The small molecule GAPDH-targeting compound TCH346 partially attenuated liver damage possibly via mitochondrial mechanisms, and independent of nuclear accumulation and aggregation of GAPDH. These findings provide a novel potential mechanism for hepatotoxicity caused by combined alcohol and acetaminophen exposure.

MeSH terms

  • Acetaminophen / toxicity*
  • Analgesics, Non-Narcotic / toxicity
  • Animals
  • Cell Nucleus / metabolism
  • Central Nervous System Depressants / toxicity
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Drug Synergism
  • Ethanol / toxicity*
  • Female
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Oxepins / pharmacology*
  • Protein Transport / drug effects*

Substances

  • Analgesics, Non-Narcotic
  • Central Nervous System Depressants
  • Oxepins
  • dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine
  • Acetaminophen
  • Ethanol
  • Glyceraldehyde-3-Phosphate Dehydrogenases