Ebselen protects brain, skin, lung and blood cells from mechlorethamine toxicity.
Nitrogen mustards are vesicants capable of burning the skin, eyes and respiratory tract of exposed individuals. While generally less toxic than sulfur mustards, these compounds have the potential for use as chemical warfare agents. Presently, no antidote exists for treatment against nitrogen mustard toxicity. The purpose of this study was to investigate the in vitro toxicity of the nitrogen mustard mechlorethamine (HN2) in four cell models: CEM-SS human T cells, A431 human skin epithelial cells, rat hippocampal astrocytes and rat pleural mesothelial cells. Furthermore, the efficacy of the synthetic seleno-organic compound ebselen (Eb) (2-phenyl-1,2- benzisoselenazol-3(2H)-one) as a cytoprotective agent against such toxicity was evaluated. Significant increases in cell viability, as assessed using an MTT assay for viability, was demonstrated when 30 microM Eb was used as a cotreatment with HN2 in all cell models tested at the following doses of HN2: A431 skin cells,10-40 microM; rat astrocytes, 20 and 40 microM; rat mesothelia, 10-40 microM; and human T cells 4-16 microM. Decreases in cell viability and toxicity to HN2 were confirmed using light and scanning electron microscopy. Membrane damage, observed with HN2 exposure, such as blebbing and loss of cell projections, was ameliorated with Eb cotreatment. Our results demonstrate a generalized protective effect observed with Eb cotreatment that suggests that this agent may have potential as an antidote for HN2 exposure and toxicity.
Hardej
Diane
D
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John's University, Queens, NY 11439, USA.
Billack
Blase
B
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D019610:Cytoprotection; D004341:Drug Evaluation; D004847:Epithelial Cells / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D054833:Isoindoles; D008466:Mechlorethamine / Q000633:toxicity*; D008853:Microscopy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010994:Pleura / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects
D001393:Azoles; D002619:Chemical Warfare Agents; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; C042986:ebselen; D008466:Mechlorethamine