Protection against 2-chloroethyl ethyl sulphide(CEES) – induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway

Sulphur 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 synthesised, 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. In the present study, the authors screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analogue, 2-chloroethyl Et sulphide (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 localisation of Nrf2 and induced expression of the GSH synthesis gene, GCLM. In addition, 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. In addition, the data 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 CDDOMe is a promising chemopreventive agent for SM toxicity in the skin.

Authors: Abel, Erika L.; Bubel, Jennifer D.; Simper, Melissa S.; Powell, Leslie; McClellan, S. Alex; Andreeff, Michael; MacLeod, Michael C.; DiGiovanni, John ;Full Sources: Toxicology and Applied Pharmacology 2011, 255(2), 176-183 (Eng) ;