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ToxSci Advance Access published online on March 30, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi165
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received January 10, 2005
Accepted March 18, 2005

In Vitro Toxicology

2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated Apoptosis of Human Promyelocytic Leukemia Cells is Preceded by Mitochondrial Cytochrome c Release in the absence of a Decrease in the Mitochondrial Membrane Potential

Mi Young Yang 1, Serrine S. Lau 2, and Terrence J. Monks 2*

1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 78712; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Science Center, Tucson, AZ 85721
2 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Science Center, Tucson, AZ 85721

* To whom correspondence should be addressed.
Terrence J. Monks, E-mail: scouser{at}pharmacy.arizona.edu


  Abstract

2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. However, the mechanisms by which TGHQ induces apoptosis are unclear, and were the focus of the present investigation. TGHQ stimulated the rapid formation (30 min) of reactive oxygen species (ROS) in HL-60 cells, and co-treatment with catalase or the antioxidant N-acetylcysteine (NAC), completely blocked TGHQ-induced apoptosis, implicating a causative role for ROS in HL-60 cell death. Western blot analysis revealed the complete disappearance of pro-caspase 9 between one and two hours after exposure of HL-60 cells to TGHQ, concomitant with the appearance of cleaved caspase 9 and increases in caspase 9 activity. The appearance of two cleaved forms of caspase 3 occurred subsequent to increases in caspase 9 activity. Levels of the anti-apoptotic Bcl-2 protein remained constant during TGHQ-induced apoptosis of HL-60 cells, but Bcl-2 S70 phosphorylation decreased. In contrast, changes in the subcellular localization of the pro-apoptotic molecule Bax was observed with a rapid (15 - 60 min) increase in the ratio of cytosolic to mitochondrial Bax. Cytochrome c release from mitochondria to the cytosol occurred subsequent to Bax translocation and the dephosphorylation of pS70 Bcl-2. However the mitochondrial inner transmembrane potential ({Delta}{psi}m) was maintained, even after cytochrome c was released from the mitochondria. Cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition pore (PTP), did not completely rescue HL-60 cells from apoptosis. Taken together, we conclude that TGHQ facilitates ROS production, alters the post-translational modification of Bcl-2 and sub-cellular localization of Bax, culminating in the release of cytochrome c and caspase activation.


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