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

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 {approx} 3-fold following exposure to CEES. Our data also suggested that CDDO-Me may actmore » 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. - Highlights: > CDDO-Me treatment increased intracellular GSH in human keratinocytes. > CDDO-Me increased cell viability following exposure to the half-mustard, CEES. > The cytoprotective effect of CDDO-Me was likely due to scavenging with endogenous GSH.« less
Authors:
; ; ; ;  [1] ;  [2] ;  [1] ;  [1]
  1. Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957 (United States)
  2. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 (United States)
Publication Date:
OSTI Identifier:
21587827
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 255; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2011.06.012; PII: S0041-008X(11)00234-1; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BRASSICA; CHEMICAL WARFARE AGENTS; CYSTEINE; DETOXIFICATION; DMSO; EDTA; EPIDERMIS; GLUTATHIONE; LIGASES; LUNGS; NAPHTHALENE; SULFIDES; SYNTHESIS; TOXICITY; VIABILITY AMINO ACIDS; ANIMAL TISSUES; AROMATICS; BODY; CARBOXYLIC ACIDS; CHALCOGENIDES; CHELATING AGENTS; CONDENSED AROMATICS; DRUGS; ENZYMES; EPITHELIUM; FOOD; HYDROCARBONS; MAGNOLIOPHYTA; MAGNOLIOPSIDA; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC SULFUR COMPOUNDS; ORGANS; PEPTIDES; PLANTS; POLYPEPTIDES; PROTEINS; RADIOPROTECTIVE SUBSTANCES; RESPIRATORY SYSTEM; RESPONSE MODIFYING FACTORS; SKIN; SULFOXIDES; SULFUR COMPOUNDS; THIOLS; VEGETABLES; WEAPONS