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Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 313:780-789
- Publication Year :
- 2005
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2005.
-
Abstract
- The mild analgesic drug acetaminophen (AAP) induces severe hepatic injury when taken at excessive doses. Recent evidence shows that the initial form of damage is through apoptosis, but this fails to go to completion and degenerates into necrosis. The aim of this study was to elucidate the mechanism through which AAP induces apoptosis using human HuH7 hepatoma cells as an in vitro model system to investigate the initial phase of AAP-induced hepatic injury. AAP-induced apoptosis in HuH7 cells as evidenced by chromatin condensation was preceded by the translocation of Bax to mitochondria and the cytoplasmic release of the proapoptotic factors cytochrome c and Smac/DIABLO. A concomitant loss of mitochondrial membrane potential occurred. Activation of the mitochondrial pathway of apoptosis led to the activation of execution caspases-3 and -7. AAP-induced apoptosis and cell death was blocked by inhibitors of caspases but not by inhibitors of calpains, cathepsins, and serine proteases. Apoptosis was unaffected by inhibitors of the mitochondrial permeability transition pore and by inhibitors of Jun NH(2)-terminal kinases, p38 mitogen-activated protein kinase, or mitogen-activated protein kinase kinase 1/2. However, pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) delayed and decreased the extent of AAP-induced apoptosis. In comparison, endoplasmic reticulum stress-induced but not prooxidant-induced apoptosis of HuH7 cells was sensitive to GSK-3 inhibition. It is concluded that AAP-induced apoptosis involves the mitochondrial pathway of apoptosis that is mediated by GSK-3 and most likely initiated through an endoplasmic reticulum stress response.
- Subjects :
- Pharmacology
Inhibitor of apoptosis domain
Programmed cell death
Carcinoma, Hepatocellular
p38 mitogen-activated protein kinases
Intrinsic apoptosis
Apoptosis
Biology
Molecular biology
Cell biology
Glycogen Synthase Kinase 3
Mitochondrial permeability transition pore
GSK-3
Cell Line, Tumor
Humans
Molecular Medicine
ASK1
Protein Kinase Inhibitors
Acetaminophen
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 313
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....e92d1fb959d921e02e831431a10c11b3