Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress.
Diepoxybutane (DEB) is the most potent metabolite of the environmental chemical 1,3-butadiene (BD), which is prevalent in petrochemical industrial areas. BD is a known mutagen and human carcinogen, and possesses multi-systems organ toxicity. We recently reported that DEB-induced cell death in TK6 lymphoblasts was due to the occurrence of apoptosis, and not necrosis. In this study, we investigated the molecular mechanisms responsible for DEB-induced apoptosis in these cells. Bax and Bak were found to be over-expressed and activated, and the mitochondrial trans-membrane potential was attenuated in cells undergoing DEB-induced apoptosis. Cytochrome c was depleted from the mitochondria of TK6 cells undergoing apoptosis, and was released into the cytosol in Jurkat T-lymphoblasts exposed to the same concentrations of DEB. Executioner caspase 3 was deduced to be activated by initiator caspase 9. DEB-induced reactive oxygen species (ROS) formation, and the ROS scavenger N-acetyl-L-cysteine effectively blocked DEB-induced apoptosis in TK6 cells. Collectively, these results demonstrate that the mitochondrial apoptotic pathway is activated to mediate DEB-induced apoptosis in human TK6 lymphoblasts. These results further demonstrate that DEB-induced apoptosis is also mediated by the DEB-induced generation of ROS. This is the first report to examine the mechanism of DEB-induced apoptosis in human lymphoblasts.
Yadavilli
Sridevi
S
Environmental Toxicology Ph.D. Program, Southern University, Baton Rouge, LA 70813, USA.
Martinez-Ceballos
Eduardo
E
Snowden-Aikens
Janana
J
Hurst
Angela
A
Joseph
Tranole
T
Albrecht
Thomas
T
Muganda
Perpetua M
PM
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053453:Caspase 9; D002460:Cell Line; D045304:Cytochromes c; D004852:Epoxy Compounds / Q000633:toxicity*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004852:Epoxy Compounds; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C007366:diepoxybutane; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9
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