Jain Anil K, Tewari-Singh Neera, Inturi Swetha, Kumar Dileep, Orlicky David J, Agarwal Chapla, White Carl W, Agarwal Rajesh
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Toxicol Appl Pharmacol. 2015 May 15;285(1):71-8. doi: 10.1016/j.taap.2015.03.009. Epub 2015 Mar 16.
Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants.
目前，对于预防芥子气（SM）和氮芥（NM）导致的皮肤损伤，尚无有效的解毒剂。SM和NM是具有潜在化学战、恐怖袭击或工业/实验室事故相关性的糜烂性毒剂。我们早期的报告已经证明了水飞蓟宾（一种天然黄酮）在逆转单功能烷基化SM类似物2-氯乙基乙基硫醚诱导的小鼠皮肤毒性作用方面的治疗效果。为了将这种效果转化到双功能烷基化糜烂性毒剂上，在此，我们对NM进行了疗效研究。在雄性SKH-1无毛小鼠背部皮肤暴露于NM 30分钟后局部应用水飞蓟宾（1或2毫克），在暴露后24、72或120小时显著减少了NM诱导的毒性损伤。具体而言，水飞蓟宾治疗导致NM诱导的表皮厚度增加、表皮死亡和剥脱、角化不全和微水疱形成呈剂量依赖性降低。较高剂量的水飞蓟宾还分别使NM诱导的髓过氧化物酶活性增加和COX-2水平增加逆转了79%和51%。此外，水飞蓟宾完全阻止了NM诱导的H2A.X磷酸化，表明DNA损伤得到逆转，这可能是一种氧化性DNA损伤，如在暴露于NM的小鼠皮肤中高水平的8-氧代脱氧鸟苷所证明的，而水飞蓟宾显著逆转了这种损伤。总之，这些发现表明水飞蓟宾减轻NM诱导的皮肤损伤是由于其对与DNA损伤、炎症、糜烂和氧化应激相关途径的影响。总之，此处呈现的结果支持将水飞蓟宾优化为一种有效治疗糜烂性毒剂所致皮肤损伤的药物。
