Journal
TOXICOLOGY IN VITRO
Volume 21, Issue 8, Pages 1429-1441Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2007.06.007
Keywords
diepoxybutane; butadiene; apoptosis; mitochondrial apoptotic pathway; human TK6 lymphoblasts; reactive oxygen species (ROS); oxidative stress; N-acetyl-L-cysteine
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Funding
- NIEHS NIH HHS [S11 ES010018, S11 ES010018-05] Funding Source: Medline
- NIGMS NIH HHS [S06 GM076530-01, S06 GM076530, S06 GM076530-010002, S06 GM076530-02] Funding Source: Medline
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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. (C) 2007 Elsevier Ltd. All rights reserved.
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