Sulfur mustard cytotoxicity

The final type of chemical toxicity that will be presented are the vesicants, chemicals that cause blisters on the skin. There are two classes of blisters that implicate different mechanisms of vesication. Intraepidermal blisters are usually formed due to the loss of intercellular attachment caused by cytotoxicity or cell death. The second class occurs within the epidermal-dermal junction (EDJ) due to chemical-induced defects in the basement membrane components. The classic chemical associated with EDJ blisters is the chemical warfare agent sulfur mustard (bis-2-chloroethyl sulfide HD). HD is a bifunctional alkylating agent that is highly reactive with many biological macromolecules, especially those containing nucleophilic groups such as DNA and proteins. 

In the review by Papirmeister et al. (1991), it was noted that sulfur mustard-induced cytotoxicity is dose dependent and that DNA appeared to be more sensitive to mustard-induced alkylation than are other cellular constituents. The low-dose effects of sulfur mustard are characterized by gen-otoxicity and inhibition of mitosis. The loss of cellular reproduction may be due to bifunctional alkylation that ultimately prevents normal DNA replication. It was hypothesized that monofunctional DNA damage might be responsible for low-dose mutagenic and possibly carcinogenic effects. 

Gross, C.L., Innace, J.K., Hovatter, R.C., Meier, H.L., Smith, W.J. (1993). Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard. Cell Biol. Toxicol. 9 259-67. 

Sawyer, T.W., Hamilton, M.G. (2000). Effect of intracellular calcium modulation on sulfur mustard cytotoxicity in cultured human neonatal keratinocytes. Toxicol. In Vitro 14 149-57. 

Meier, H.L., Johnson, J.B. (1992). The determination and prevention of cytotoxic effects induced in human lymphocytes by the alkylating agent 2,2 -dichlorodiethyl sulfide (sulfur mustard, HD). Toxicol. Appl. Pharmacol. 113 234-9. 

Petrali, J.P., Oglesby, S.B., Meier, H.L. (1990). Ultrastructural correlates of the protection afforded by niacinamide against sulfur mustard-induced cytotoxicity of human lymphocytes in vitro. Ultrastruct. Pathol. 14 253-62. 

B. Vesicants (blister agents). Nitrogen and sulfur mustards and Lewisite are cytotoxic alkylating agents Lewisite combines with thiol moieties in many enzymes and also contains trivalent arsenic. 

Doebler, J. A. Blockade of sulfur mustard cytotoxicity in human epidermal keratinocytes with the purinergic receptor antagonist suramin. Vet. Human Toxicol. 2003, 45, 14-17. 

First, sulfur mustard, a vesicant warfare agent, was produced and used in World War I. Mustards alkylate a wide range of biologically important molecules producing c)dostatic, mutagenic, and cytotoxic effects. In 1936, just before the start of World War II, tabun was synthesized and then produced as the first nerve CWA. Nerve agents inhibit acetylcholinesterase (AChE) throughout... 

Gross, C.L., Nealley, E.W, Nipwoda, M.T., et al., 2006. Pretreatment of human epidermal keratinocytes with D,L-sulforaphane protects against sulfur mustard cytotoxicity. Cutan. Ocul. Toxicol. 25, 155-163. 

Rappeneau, S., Baeza-Squiban, A., Marano, F., Calvet, J. (2000). Efficient protection of human bronchial epithelial cells against sulfur and nitrogen mustard cytotoxicity using drug combinations. Toxicol. Sci. 58 153-60. 

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