Acetaminophen induces ER dependent signaling in mouse liver.
Role of endoplasmic reticulum (ER) in liver injury by acetaminophen (AAP) was studied in vivo in mice. Sublethal dose of AAP resulted in a decrease in microsomal total glutathione and in the reduced-to-total glutathione ratio; redox state of thiols of ER resident oxidoreductases ERp72, PDI was shifted towards the oxidized form; ER stress-responsive transcription factor ATF6 was activated. Transcriptional activation and elevated expression of GADD153/CHOP, an ER stress-responsive proapoptotic transcription factor, was observed upon AAP addition. Transient activation of the ER-resident caspase-12 was shown followed by an elevation in procaspase-12 level. Caspase-3 and caspase-8 activation could not be detected. AAP treatment resulted in an increased apoptosis of hepatocytes. Buthionine-sulfoximine treatment was unable to mimic the effects by AAP indicating that glutathione depletion itself is insufficient to provoke apoptosis. The results show that intraluminal redox imbalance of the ER and consequential activation of signaling processes and proapoptotic events are involved in hepatocellular damage caused by AAP overdose.
Nagy
Gábor
G
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest POB 260, Hungary.
Kardon
Tamás
T
Wunderlich
Lívius
L
Szarka
András
A
Kiss
András
A
Schaff
Zsuzsa
Z
Bánhegyi
Gábor
G
Mandl
József
J
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D000082:Acetaminophen