BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury.
It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.
Nagy
Gábor
G
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, HAS Pathobiochemistry Research Group, H-1444 Budapest POB 260, Hungary.
Szarka
András
A
Lotz
Gábor
G
Dóczi
Judit
J
Wunderlich
Lívius
L
Kiss
András
A
Jemnitz
Katalin
K
Veres
Zsuzsa
Z
Bánhegyi
Gábor
G
Schaff
Zsuzsa
Z
Sümegi
Balázs
B
Mandl
József
J
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D004721:Endoplasmic Reticulum; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D010091:Oximes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D000637:Transaminases / Q000097:blood
D010091:Oximes; D010880:Piperidines; D000082:Acetaminophen; D000637:Transaminases; D020169:Caspases; C405586:BGP 15