Mustard vesicating agent–induced toxicity in the skin tissue and silibinin as a potential countermeasure

Abstract

Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent–induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents.

Combination of ebselen and hydrocortisone substantially reduces nitrogen mustard-induced cutaneous injury

“…EVRs are reported to occur in up to 6% of patients receiving intravenous cancer chemotherapy ( Bertelli, 1995 , Cassagnol and McBride, 2009 ). Indeed, HN2 exhibits a very complex mechanism of toxicity that involves many macromolecules and cell signaling pathways ( Korkmaz et al, 2006 , McManus and Huebner, 2005 , Tewari-Singh and Agarwal, 2016 ). Our group previously reported that HN2 triggers numerous responses in cultured skin cells in vitro , including damaged nuclear DNA, increased lipid peroxidation and apoptosis via activation of caspases 3 and 9 ( Lulla et al, 2013 , Pino and Billack, 2008 , Pino et al, 2014 ), and that the organoselenium compound ebselen (EB-1) reduces the toxicity of both HN2 ( Hardej and Billack, 2007 , Lulla et al, 2014 ) and the sulfur half mustard CEES in vitro ( Pino et al, 2013 ).…”

Phosgene oxime: Injury and associated mechanisms compared to vesicating agents sulfur mustard and lewisite

“…There are no effective approved antidotes available for SM. Although a number of compounds including anti-oxidants, protease inhibitors, PARP inhibitors, angiogenesis inhibitors, calcium modulators, anti-inflammatory agents, and flavanones have been shown to be effective to various extents in laboratory studies (Balszuweit et al, 2013; Goswami et al, 2016a; Kadar et al, 2014; Kadar et al, 2009; Laskin et al, 2010; McElroy and Day, 2016; Paromov et al, 2007; Smith, 2009; Tewari-Singh and Agarwal, 2016; Weinberger et al, 2016). There is no specific antidote available against CX-induced injuries and the treatment is mostly supportive to reduce symptoms, prevent infections and help healing.…”

Development of a method for the derivatization of ethanolamines and its application to sand samples

“…2 Nitrogen mustards are specific by their potent alkylating effects 3 and they interact with a number of biomolecules and a characteristic manifestation of poisoning is severe blister formation. 4 These are controlled substances, however, the synthetic pathways are quite simple, precursors are available, and nitrogen mustards therefore still pose an actual threat. The hydrolysis degradation products are ethyl diethanolamine (EDEA), methyl diethanolamine (MDEA), and triethanolamine (TEA).…”