Sulfur mustard mediators

Hinshaw, D.B., Lodhi, I.J., Hurley, L.L., Atkins, K.B., Dabrowska, M.I. (1999). Activation of poly [ADP-ribose] polymerase in endothelial cells and keratinocytes role in an in vitro model of sulfur mustard-mediated vesication. Toxicol. Appl. Pharmacol. 156 17-29. 

Lodhi IJ, Sweeney JF, Clift RE et al. (2001). Nuclear dependence of sulfur mustard-mediated cell death. Toxicol Appl Pharmacol, 170, 69-77. 

The metabolism of nerve agents is much simpler than that of sulfur mustard. The major pathway for elimination is via enzyme-mediated hydrolysis by esterases, plus some chemical hydrolysis, as shown in Figure 10. In the case of the methylphosphonofluoridates and V agents, the major product is an alkyl methylphosphonic acid (alkyl MPA) (16). A small fraction of the nerve agent binds... 

Sulfur mustard inhibited DNA synthesis in mouse lymphoma cells (Crathom and Roberts, 1965), HeLa cells (Crathom and Roberts, 1966), and L-strain mouse fibroblasts (Walker and Thatcher, 1968). It also induced chromosomal aberrations in cultured rat lymphosarcoma and mouse lymphoma cells (Scott et al., 1974), and chromosomal aberrations and reverse mutations in male BDF mice in a host-mediated assay using murine leukemia L5178Y/Asn cell hne as an indicator (Capizzi et al., 1973). 

Buxton, K.L., Babin, M.C., Ricketts, K.M., Gazaway, M.Y., Blank, J.A., Danne, M.M. (2000). Characterization of sulfur mustard-induced proinflammatory mediator response in mouse ears. Toxicologist 54 213. 

Elsayed, N., Omaye, S., Klain, G., Korte, D., Jr. (1992). Free radical-mediated lung response to the monofimctional sulfur mustard butyl 2-chloroethyl sulfide after subcutaneous injection. Toxicology 72 153-65. 

Lefkowitz, L.J., Smith, W.J. (2002). Sulfur mustard-induced arachidonic acid release is mediated hy phospholipase D in human keratinoc)4es. Biochem. Biophys. Res. Commun. 295 1062-7. 

Rikimaru, T., Nakamura, M. et al. (1991). Mediators, initiating the inflammatory response, released in organ culture by fullthickness human skin explants exposed to the irritant, sulfur mustard. J. Invest. Dermatol. 96 888-97. 

Simbulan-Rosenthal, C.M., Ray, R. et al. (2006). Calmodulin mediates sulfur mustard toxicity in human keratmoc des. 

Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard (Rosenthal et al, 2000). It was tested whether calmodulin mediates the mitoehondrial apoptotic pathway induced by SM in human keratinoeytes. Of the three human CaM genes, the predominant form expressed was CaMl. These results indicate that CaM, ealeineurin, and Bad also play a role in SM-induced apoptosis, and may therefore be targets for therapeutic intervention to reduce SM injury (Simbulan-Rosenthal et al, 2006). 

Simbulan-Rosenthal, C.M., Ray, R., Benton, B., Soeda, E., Daher, A, Anderson, D., Smith, W.J., Rosenthal, D.S. (2006). Calmodulin mediates sulfur mustard toxicity in human kera-tinocytes. Toxicology 227 21-35. 

A previous report has implicated a role of calpain in mediating the tissue injury caused by the chemical threat agent sulfur mustard. Specifically, tissue homogenates from mouse ear skin exposed to sulfur mustard displayed a marked increase in calpain activity (170% increase 24 h after treatment Powers et al. 2000). These findings underscore the need to identify effective antiproteases with therapeutic use in reducing, or eliminating, tissue injuries. Since excitotoxicity is related directly to calpain activation, it can be surmised that sulfur mustard exposures may be linked to excitotoxicity. 

Calvet JH, Gascard JP, Delamanche S, Brink C. Airway epithelial damage and release of inflammatory mediators in human lung parenchyma after sulfur mustard exposure. Hum Exp Toxicol. 1999 Feb 18(2) 77-81)... 

Shakarjian, M.P., Heck, D.E., Gray, J.P., et al., 2010. Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. Toxicol. Sci. 114, 5-19. 

Jain, A.K., Tewari-Singh, N., Gu, M., et al., 2011. Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin. Toxicol. Lett. 205, 293-301. 

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