TY - JOUR
T1 - Protection against 2-chloroethyl ethyl sulfide (CEES) - induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway
AU - Abel, Erika L.
AU - Bubel, Jennifer D.
AU - Simper, Melissa S.
AU - Powell, Leslie
AU - McClellan, S. Alex
AU - Andreeff, Michael
AU - MacLeod, Michael C.
AU - DiGiovanni, John
N1 - Funding Information:
We thank Stephanie Tomlinson, Hilary Graham, and Joi Holcomb for assistance with manuscript preparation. We also thank Collin White for his helpful discussions concerning the reduced GSH assay. This work was funded by the National Institutes of Health CounterACT Program through the National Institute of Neurological Disorders and Stroke (award # U01NS058191 ) and by an NIEHS Center grant ( P30ES007784 ).
PY - 2011/9/1
Y1 - 2011/9/1
N2 - Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100. years ago. Due to its toxic effects on the eyes, lungs, and skin, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. SM exposed skin develops fluid filled bullae resulting from potent cytotoxicity of cells lining the basement membrane of the epidermis. Currently, there are no antidotes for SM exposure; therefore, chemopreventive measures for first responders following an SM attack are needed. Glutathione (GSH) is known to have a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. Therefore, we screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analog, 2-chloroethyl ethyl sulfide (CEES). Using NCTC2544 human keratinocytes, we found that both sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of the GSH synthesis gene, GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells and preserved their viability by ~. 3-fold following exposure to CEES. Our data also suggested that CDDO-Me may act additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES. These results suggest that CDDO-Me is a promising chemopreventive agent for SM toxicity in the skin.
AB - Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100. years ago. Due to its toxic effects on the eyes, lungs, and skin, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. SM exposed skin develops fluid filled bullae resulting from potent cytotoxicity of cells lining the basement membrane of the epidermis. Currently, there are no antidotes for SM exposure; therefore, chemopreventive measures for first responders following an SM attack are needed. Glutathione (GSH) is known to have a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. Therefore, we screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analog, 2-chloroethyl ethyl sulfide (CEES). Using NCTC2544 human keratinocytes, we found that both sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of the GSH synthesis gene, GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells and preserved their viability by ~. 3-fold following exposure to CEES. Our data also suggested that CDDO-Me may act additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES. These results suggest that CDDO-Me is a promising chemopreventive agent for SM toxicity in the skin.
KW - CDDO-Me
KW - Cytotoxicity
KW - Glutathione
KW - Keratinocytes
KW - Sulfur mustard
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U2 - 10.1016/j.taap.2011.06.012
DO - 10.1016/j.taap.2011.06.012
M3 - Article
C2 - 21723306
AN - SCOPUS:80051586051
SN - 0041-008X
VL - 255
SP - 176
EP - 183
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 2
ER -