Sulfur mustards mechanism

Field First Aid Decontaminate At Once for All Exposed Victims Although sulfur mustards cause cellular changes within minutes of contact, the onset of pain and other clinical effects are delayed for one to twenty-four hours. Sulfur mustards are alkylating agents that may cause bone marrow suppression and neurologic and gastrointestinal toxicity. However, the biochemical mechanisms of action are not clearly understood by anyone. The death rate from exposure to sulfur mustard during World War I was 2-3 percent,... 

The above evidence should not be interpreted as meaning that hydrolytic dehalogenation can never be demonstrated unambiguously. Indeed, the next subsection will document reactions of multiple dehalogenation that are only consistent with a hydrolytic mechanism. But before doing so, we examine here the hydrolysis of medicinal nitrogen mustards and of their sulfur analogue, the infamous sulfur mustard. 

The mechanism of mutagenesis by sulfur mustard (and other mustards) involves the alkylation of DNA. As a bifunctional alkylating agent, sulfur mustard causes cross-linkage of DNA strands, as well as monofunctional alkylation products.19 Sulfur mustard and nitrogen mustard have been used In mutation studies In a variety of organisms, but data on the relative frequencies of induction of different alky-... 

T. A. Connors, "Mechanism of Action of 2-Chloroethyl Derivatives, Sulfur Mustards, Epoxides and Aziridines" in "Antineoplastic and Immunosuppresive Agents" Part II, A. C. Sartorelli and D. J. Johns Eds., Springer-Verlag Berlin-Heidelberg New York, 1975, p. 18. 

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. 

The mechanism of action of sulfur mustard is multifaceted and complex, and has been reviewed in some detail by Papirmeister et al. (1991), Hurst and Smith (2008), and Smith et al. (2008). Efforts to understand the mechanisms of sulfur mustard toxicity are ongoing. Basically, sulfur mustard disrupts the interface of the epidermis and basement membrane causing blistering between the epidermis and dermis. Both immediate (immediate cell membrane damage) and delayed phases (secondary effects resulting from inflammatory responses, DNA damage, vascular leakage) have been described for sulfur mustard-induced dermal effects (Somani and Babu, 1989). Many of the toxic effects of sulfur mustard can be attributed to oxidative stress. 

Among the most studied mechanisms of sulfur mustard toxicity are thiol depletion resulting in intracellular calcium... 

Sulfur mustard-induced lipid peroxidation is a function of glutathione (GSH) depletion. For this mechanism, depletion of GSH results in an accumulation of reactive oxygen species via hydrogen peroxide-dependent processes (Miccadei et al., 1988). The oxygen radicals react with membrane phospholipids forming lipid peroxides that alter membrane structure resulting in membrane breakdown. 

Casillas and Babin, unpublished). Finally, inflammatory cell infiltration, which may occur about a day after exposure, may also play a role in delaying SM wound healing (Maumenee and Schloz, 1948). The sheer number of potential target areas in a multilayered, multicell organ that may be affected by sulfur mustard make the task of determining SM s exact mechanism of action quite difficult. 

Martens, M.E., Smith, W.J. (2008). The role of NAD depletion in the mechanism of sulfur mustard-induced metabolic injury. J. Toxicol. Cutan. Ocul. Toxicol. 27 41-53. 

Papirmeister, B., Feister, A.J., Robinson, S.I., Ford, R.D. (1991c). The sulfur mustard injury description of lesions and resulting incapacitation. a Medical Defense Against Mustard Gas Toxic Mechanisms and Pharmacological Implications, pp. 21-3. CRC Press, Boca Raton, FL. 

Ray, R., Majerus, B.J., Munavalli, G.S., Petrali, J.P. (1993). Sulfur mustard-induced increase in intracellular calcium a mechanism of mustard toxicity. Proceedings of the U.S. Army Medical Bioscience Review, pp. 267-76. 

Figure 50.4 depicts the basic chemical mechanism by which sulfur mustard incurs the primary damage to biological molecules which results in subsequent damage to cells, tissues, and organs. 

FIGURE 50.4. Sulfur mustard, its structure, mechanism of action, and targets of adduct formation. A Mechanism of reaction of sulfur mustard and nucleotide guanine. B Sites of alkylation hy sulfur mustard. Arrows mark identified targets in nucleotides and amino acid histidine. 

Within cells, sulfur mustard forms adducts with DNA, primarily those described in Toxicity of sulfur mustard, above. Adducts can also be formed with nucleophilic sites of amino acids and proteins. Contrary to DNA adducts, there is no specific mechanism to reverse protein adduct formation. For this reason, there is a strong forensic interest in the detection of protein adducts of sulfur mustard as these may provide evidence of sulfur mustard exposure for prolonged periods after the incident. 

Meier, H.L., Millard, C., Moser, J. (2000). Poly(ADP-ribose) polymerase inhibitors regulate the mechanism of sulfur mustard-initiated cell death in human lymphocytes. J. Appl. Toxicol 20 S93-100. 

Smith, K.J., Hurst, C.G., Moeller, R.B., Skelton, H.G., Sidell, F.R. (1995). Sulfur mustard its continuing threat as a chemical warfare agent, the cutaneous lesions induced, progress in understanding its mechanism of action, its long-term health effects, and new developments for protection and therapy. J. Am. Acad. Dermatol. 32 16S-16. 

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