QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.081364v1 313/2/780    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Macanas-Pirard, P. Articles by Kass, G. E. N. Search for Related Content PubMed PubMed Citation Articles by Macanas-Pirard, P. Articles by Kass, G. E. N.

TOXICOLOGY

Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells

School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, United Kingdom (P.M.-P., N.-S.Y., R.H.H., G.E.N.K.); and Cellular Pathology and Toxicology, GlaxoSmithKline, Ware, United Kingdom (P.C.L., J.C.H.)

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 NH₂-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.

Address correspondence to: Dr. George E. N. Kass, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. E-mail: g.kass{at}surrey.ac.uk

This article has been cited by other articles:

				I. Manov, Y. Bashenko, A. Eliaz-Wolkowicz, M. Mizrahi, O. Liran, and T. C. Iancu High-Dose Acetaminophen Inhibits the Lethal Effect of Doxorubicin in HepG2 Cells: The Role of P-glycoprotein and Mitogen-Activated Protein Kinase p44/42 Pathway J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1013 - 1022. [Abstract] [Full Text] [PDF]

				G. Kroemer, L. Galluzzi, and C. Brenner Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev, January 1, 2007; 87(1): 99 - 163. [Abstract] [Full Text] [PDF]

				M. A. Salako, M. J. Carter, and G. E. N. Kass Coxsackievirus Protein 2BC Blocks Host Cell Apoptosis by Inhibiting Caspase-3 J. Biol. Chem., June 16, 2006; 281(24): 16296 - 16304. [Abstract] [Full Text] [PDF]

				A. Natoni, G. E. N. Kass, M. J. Carter, and L. O. Roberts The mitochondrial pathway of apoptosis is triggered during feline calicivirus infection J. Gen. Virol., February 1, 2006; 87(2): 357 - 361. [Abstract] [Full Text] [PDF]

				H. Jaeschke and M. L. Bajt Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death Toxicol. Sci., January 1, 2006; 89(1): 31 - 41. [Abstract] [Full Text] [PDF]

				J. G. Pastorino, J. B. Hoek, and N. Shulga Activation of Glycogen Synthase Kinase 3{beta} Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity Cancer Res., November 15, 2005; 65(22): 10545 - 10554. [Abstract] [Full Text] [PDF]

				H. Jaeschke Comments on "Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells" J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1401 - 1402. [Full Text] [PDF]

				G. E. N. Kass Response: Comments on "Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells" J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1403 - 1404. [Full Text] [PDF]