2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog.
Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. Topical exposure to high concentrations of 2-(chloroethyl) ethyl sulfide (CEES), a monofunctional analog of SM, also produces severe skin lesions in mice. Utilizing a genetically engineered mouse strain, Big Blue, that allows measurement of mutation frequencies in mouse tissues, we now show that topical treatment with much lower concentrations of CEES induces significant dose- and time-dependent increases in mutation frequency in mouse skin; the mutagenic exposures produce minimal toxicity as determined by standard histopathology and immunohistochemical analysis for cytokeratin 6 and the DNA-damage induced phosphorylation of histone H2AX (γ-H2AX). We attempted to develop a therapeutic that would inhibit the CEES-induced increase in mutation frequency in the skin. We observe that multi-dose, topical treatment with 2,6-dithiopurine (DTP), a known chemical scavenger of CEES, beginning 1h post-exposure to CEES, completely abolishes the CEES-induced increase in mutation frequency. These findings suggest the possibility that DTP, previously shown to be non-toxic in mice, may be useful as a therapeutic agent in accidental or malicious human exposures to SM.
Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA.
Stephen
S
Boulware
Tammy
T
Fields
Elizabeth
E
McIvor
K Leslie
KL
Powell
Erika L
EL
Abel
Karen M
KM
Vasquez
Michael C
MC
MacLeod
D000279:Administration, Cutaneous; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005818:Genetic Engineering; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D053553:Keratin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009151:Mustard Gas / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D016296:Mutagenesis / Q000187:drug effects*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
D002619:Chemical Warfare Agents; D006657:Histones; D053553:Keratin-6; D009151:Mustard Gas; D011687:Purines; C070898:2,6-dithiopurine; C031278:2-chloroethyl ethyl sulfide; C475961:gamma-H2AX protein, mouse