Adducts with Keratin

Lewisite is the most important of the organo-arseni-cal CW agents. Exposure to lewisite is quite painful, and onset of symptoms occurs rapidly (seconds to minutes) (31) in contrast to sulfur mustard for which a latency period occurs of several hours between exposure and symptoms (32). Although it is not known to have been used as a CW agent, lewisite is still considered a potential threat due to the relative ease of production and its rapid onset of action. Moreover, substantial stockpiles of lewisite are present in the United States, Russia, and in China abandoned by the Japanese Imperial Army. This may constitute a potential hazard for public health (33). The toxicity of lewisite is inter alia caused by the high affinity for the vicinal di-thiol system present in dihydrolipoic acid, a component of the pyruvate dehydrogenase complex, as is the case for other arsenicals (34). This prevents the formation of acetyl coenzyme A from pyruvate. 

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G.P. Van der Schans, D. Noort, R.H. Mars-Groenendijk, A. Fidder, L.F. Chau, L.P.A. De Jong and H.P. Benschop, Immunochemical detection of sulfur mustard adducts with keratins in the stratum corneum of human skin, Chem. Res. Toxicol., 15, 21-25 (2003). 

A direct detection method was recently developed for these adducts in stratum comeum of human skin based on immunofluorescence microscopy (30). Three partial sequences of keratins containing glutamine or asparagine, adducted with a 2-hydroxyethyl-thioethyl group at the omega-amide function, were synthesized and used as antigens for raising antibodies. After immunization, monoclonal antibodies were obtained with affinity for keratin isolated from human callus exposed to 50 xM sulfur mustard (see Plate 1). In contrast to the immunochemical... 

The use of sulfur mustard as a vesicant CW agent implies that proteins of the skin are a primary target. It was found that upon exposure of human callus to [14C]sulfur mustard, a significant part of the radioactivity was covalently bound to keratin (30). Most of the radioactivity (80%) bound to keratin could be removed by treatment with alkali, indicating the presence of adducts to glutamic and/or aspartic acid residues. 

Figure 4. Immunofluorescence microscopy of a cross-section of human skin exposed to saturated sulfur mustard vapor (1 min at 27 °C Ct 1040 mg.min.nr3 A) and of unexposed skin (B), using monoclonal antibody 1H10, directed against sulfur mustard adducts to human keratin, in a 1/50 dilution. The photographs are composed from an image obtained for FITC fluorescence (mainly emanating from the stratum corneum green) and from an image obtained for propidium iodide fluorescence representing DNA (red) in the same cross-section. (Reprinted with permission from G. R van der Schans et al., Chem. Res. Toxicol. 15, 21-25, 2002. Copyright (2002) American Chemical Society).

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