Effects of selected arginine analogues on sulphur mustard toxicity in human and hairless guinea pig skin keratinocytes.
The toxicity of sulphur mustard (HD) was characterized in first passage cultures of human neonatal foreskin keratinocytes and then several arginine analogues were investigated to ascertain their efficacies in protecting against HD toxicity in this system. d- and l-nitroarginine methyl ester (d/l-NAME), l-phosphoarginine, and l-nitroarginine were all found to confer concentration-related protective effects against HD in confluent cultures. l-NAME was used to further characterize this protection and was only effective in cultures that were not actively proliferating. This compound was also found to be efficacious when added to the cultures up to several hours after HD exposure, although its continued presence was required in order for protection to be effective. The protective effects of l-thiocitrulline (l-TC) against HD toxicity were also assessed. This arginine analogue was extremely potent in preventing HD toxicity in actively proliferating, just-confluent, and postconfluent cultures in a concentration-dependent fashion (0.1-15 mM), with little HD toxicity apparent at high l-TC concentrations. Protection was prophylactic in nature, with l-TC having almost maximal effect when added to the cultures only 1 min prior to HD culture exposure. Efficacy then declined rapidly so that no protection was evident when l-TC was added 30 min post-HD. The effects of this drug were persistent, with no decrease in protective efficacy up to 4 days after HD exposure, even when l-TC was removed from the cultures. l-TC did not protect against the antimitotic effects of HD; while l-TC-protected cells were subcultured successfully, they displayed no clonogenic activity. Although l-TC is closely related structurally to protective nitroarginine derivatives, the characteristics of l-TC protection against HD were markedly different and suggest that they exert their protective activities at different sites. Administration of l-NAME and l-TC by a variety of routes did not result in consistent protection against topical vapor challenges of HD in hairless guinea pigs. However, both compounds were effective in preventing the toxicity of HD in primary cultures of hairless guinea pig skin keratinocytes, indicating that species differences were not likely to be responsible for the poor efficacy of these compounds in vivo.
Sawyer
T W
TW
Therapy Group, Defence Research Establishment Suffield, Medicine Hat, Alberta, T1A 8K6, Canada. Thomas.Sawyer@dres.dnd.ca
Risk
D
D
D000287:Administration, Topical; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002478:Cells, Cultured; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D003879:Dermatologic Agents / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D009151:Mustard Gas / Q000633:toxicity*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D003879:Dermatologic Agents; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; C086715:thiocitrulline; C015441:phospho-L-arginine; D019335:Nitroarginine; D002956:Citrulline; D001120:Arginine; D013890:Thiourea; D009151:Mustard Gas; D019331:NG-Nitroarginine Methyl Ester