title: Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin.
abstract: 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.
authors: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Anil K
authors: AK
authors: Jain
authors: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Neera
authors: N
authors: Tewari-Singh
authors: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Swetha
authors: S
authors: Inturi
authors: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Dileep
authors: D
authors: Kumar
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: David J
authors: DJ
authors: Orlicky
authors: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Chapla
authors: C
authors: Agarwal
authors: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045USA.
authors: Carl W
authors: CW
authors: White
authors: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: Rajesh.Agarwal@UCDenver.edu.
authors: Rajesh
authors: R
authors: Agarwal
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000279:Administration, Cutaneous; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019610:Cytoprotection; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000378:metabolism; D007509:Irritants / Q000633:toxicity*; D008297:Male; D008466:Mechlorethamine / Q000633:toxicity*; D008812:Mice, Hairless; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000931:Antidotes; D051546:Cyclooxygenase 2; D003849:Deoxyguanosine; D006657:Histones; D007509:Irritants; D008466:Mechlorethamine; D009195:Peroxidase; D000077385:Silybin; D012838:Silymarin; C077623:Ptgs2 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: Microvesication; Nitrogen mustard; Oxidative DNA damage; SKH-1 hairless mice; Silibinin; Skin