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

Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 06/2011; 255(2):176-83. DOI: 10.1016/j.taap.2011.06.012
Source: PubMed


Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100years 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.

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    • "Additional studies with other Nrf2-activating compounds suggest a beneficial effect of Nrf2 activation in response to various environmental toxins. For example, ketoconazole, an activator of the aryl hydrocarbon receptor (AHR) and of Nrf2, protected cultured human keratinocytes from ROS and interleukin-8 production in response to benzo[a]pyrene treatment [42], and methyl-2-cyano-3,12-dioxoo- leana-1,9-dien-28-oate (CDDO-me) protected keratinocytes from the toxicity of a sulfur mustard analogue [43]. The importance of the KEAP1–Nrf2 pathway, rather than the BACH1–Nrf2 pathway, in the protective activity of Nrf2-activating compounds was demonstrated by the finding that knockdown of KEAP1, but not of BACH1 in HaCaT keratinocytes, provided strong resistance to acrolein, chlorambucil, cumene hydroperoxide, and menadione [44]. "
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    ABSTRACT: The skin is frequently exposed to environmental challenges, such as UV irradiation, toxic chemicals or mechanical wounding. These insults cause an increase in the levels of reactive oxygen species, resulting in oxidative stress and concomitant inflammation, skin aging and even cancer development. Therefore, an efficient antioxidant defense strategy is of major importance in this tissue. Since the NRF2 transcription factor regulates a battery of genes involved in the defense against reactive oxygen species and in compound metabolism, it plays a key role in skin homeostasis, repair and disease. In this review we summarize current knowledge on the expression and function of NRF2 in normal skin, its role in the acute and chronic UV response as well as in the pathogenesis of epithelial skin cancer and of different inflammatory skin diseases. Finally, we discuss the potential of NRF2-activating compounds for skin protection under stress conditions and for the treatment of major human skin disorders. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 04/2015; DOI:10.1016/j.freeradbiomed.2015.04.018 · 5.74 Impact Factor
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    • "It can occur either spontaneously or be mediated by glutathione-Stransferases (Kinsey and Grant, 1947; Davison et al., 1961; Black et al., 1992a,b; Abel et al., 2011). The reactivity of SM toward GSH is so large that a phenomenon of GSH depletion was observed both in in vitro (Ray et al., 1995; Gross et al., 1997; Amir et al., 1998) and in vivo models exposed to SM (Gautam and Vijayaraghavan, 2007; Jafari, 2007; Vijayaraghavan et al., 2008; Pohanka et al., 2013). "
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    ABSTRACT: Sulfur mustard (SM) is an old chemical warfare but it remains a threat to both militaries and civilians. SM mainly targets skin, eyes and lungs and diffuses to internal organs. At the molecular level, SM is able to damage DNA through the formation of monoadducts and biadduct. Glutathione (GSH) is another critical target of SM in cells since it is part of the detoxification mechanism against alkylating agents. In the present work, we investigated whether SM could form covalent bonds simultaneously with a DNA base and the sulfhydryl group of GSH. The expected guanine adduct, S-[2-(N7-guanyl)-ethylthioethyl]-glutathione (N7Gua-ETE-GSH), was synthesized and detected in several tissues of SKH-1 mice exposed to 60 mg/kg of SM in the dorsal-lumbar region. N7Gua-ETE-GSH was detected in all organs studied, except in the liver. The tissue exhibiting the highest levels of N7Gua-ETE-GSH was skin, followed by brain, lungs, kidneys and spleen. N7Gua-ETE-GSH was detected in skin, brain and lungs as long as two weeks after exposure. The persistence was less in other organs. The observation of the formation of N7Gua-ETE-GSH in vivo confirms the variety of damages induced by SM in DNA. It also provides another example of the formation of DNA adducts involving glutathione following in vivo exposure to bifunctional alkylating compounds.
    Toxicology Letters 02/2015; 233(1):1-7. DOI:10.1016/j.toxlet.2015.01.001 · 3.26 Impact Factor
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    • "(Abel et al., 2011; Black et al., 1992a, 1992b; Davison et al., 1961; Kinsey and Grant, 1947 "

    Toxicology and Applied Pharmacology 01/2014; · 3.71 Impact Factor
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