Ethanol rapidly causes activation of JNK associated with ER stress under inhibition of ADH.
Acute ethanol loading causes oxidative stress to activate cell-death signaling via c-Jun NH2-terminal kinase (JNK) in livers. JNK are stimulated under conditions of endoplasmic reticulum (ER) stress which causes programmed cell death. However, no remarked cell death was observed in acute ethanol intoxication. Akt, one of the cell survival protein kinases, may be activated under ethanol loading. The aim of this study was to estimate activation of JNK and ER stress, role of ethanol metabolism on the activation, and association of JNK with Akt under acute ethanol loading using the perfused rat liver system. Activation of JNK or Akt and association of JNK and Akt with JNK interacting protein 1 were estimated by immunoprecipitation and immunoblotting. Expression of 78 kDa glucose-regulated protein (GRP78) mRNA, a biomarker of ER stress, was detected by quantitative real-time RT-PCR. Activations of JNK and Akt were enhanced by co-treatment with ethanol and a classical inhibitor of alcohol dehydrogenase (ADH). Addition of an antioxidant reduced the activation of JNK. Ethanol loading with ADH inhibition causes down-regulation of GRP78 mRNA levels. Therefore, these findings suggest first revelation that inhibition of ethanol metabolism complicates oxidative and ER stresses produced by ethanol.
Nishitani
Yoko
Y
Department of Legal Medicine, Sapporo Medical University School of Medicine, S-1 W-17, Chuo-ku, Sapporo 060-8556, Japan.
Matsumoto
Hiroshi
H
D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D018832:Molecular Chaperones / Q000096:biosynthesis; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D002492:Central Nervous System Depressants; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4