title: Differential changes in MAP kinases, histone modifications, and liver injury in rats acutely treated with ethanol.
abstract: BACKGROUND
  Acute ethanol is known to affect cells and organs but the underlying molecular mechanisms are poorly explored. Recent developments highlight the potential importance of mitogen-activated protein kinases, MAPKs (i.e., ERK1/2, p38, and JNK1/2) signaling, and histone modifications (i.e., acetylation, methylation, and phosphorylation) in the actions of ethanol in hepatocytes. We have therefore investigated significance of these molecular steps in vivo using a model in which rats were acutely administered ethanol intraperitoneally (IP).
  
  
  METHODS
  Ethanol was administered IP (3.5 gm/kg body weight) to 12-week-old male Sprague-Dawley rats. Liver was subsequently removed at 1 and 4 hours. Serum was used for alcohol and ALT assays. At the time of the removal of liver, small portions of each liver were formalin-fixed and stained with hematoxylin and eosin (H&E) and used for light microscopy. Western blot analysis was carried out with specific primary antibodies for various parameters.
  
  
  RESULTS
  There were clear differences at 1 and 4 hours in blood ethanol, ALT, steatosis, and cleaved caspase 3. Apoptosis at 1 hour was followed by necrosis at 4 hours. Acute alcohol elicited a marked increase in the phosphorylation of ERK1/2 and moderate increases in the phosphorylation of p38 MAPK and JNK. Temporally different phosphorylation of histone H3 at ser-10 and ser-28 occurred and acetylation of histone H3 at lys 9 increased progressively.
  
  
  CONCLUSIONS
  There were distinct differences in the behavior of the activation of the 3 MAP kinases and histone modifications after acute short exposure of liver to ethanol in vivo. Although all 3 MAPKs were rapidly activated at 1 hour, the necrosis, occurring at 4 hours, correlated to sustained activation of ERK1/2. Transient activation of p38 is associated with rapid phosphorylation of histone H3, whereas prolonged activation of ERK1/2 is correlated to persistent histone H3 acetylation.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.forename: Taryn T
authors.initials: TT
authors.lastname: James
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Jackson
authors.forename: Shivendra D
authors.initials: SD
authors.lastname: Shukla
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006657:Histones; D000431:Ethanol; D000410:Alanine Transaminase; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3