title: Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346-Insensitive Nuclear Translocation of GAPDH.
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.
authors: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, 27599, United States of America.
authors: Natasha T
authors: NT
authors: Snider
authors: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors: Daniel A
authors: DA
authors: Portney
authors: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, 27599, United States of America.
authors: Helen H
authors: HH
authors: Willcockson
authors: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors: Dhiman
authors: D
authors: Maitra
authors: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors: Hope C
authors: HC
authors: Martin
authors: Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors: Joel K
authors: JK
authors: Greenson
authors: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, United States of America.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.|Veterans Administration Ann Arbor Health Care System, Ann Arbor, MI, 48105, United States of America.
authors: M Bishr
authors: MB
authors: Omary
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010082:Oxepins / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects*
chemical_list: D018712:Analgesics, Non-Narcotic; D002492:Central Nervous System Depressants; D010082:Oxepins; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; D000082:Acetaminophen; D000431:Ethanol; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases