l-thiocitrulline: A potent protective agent against the toxicity of sulphur mustard in vitro.
Previous studies in this laboratory have shown that the well-characterized arginine analogue nitric oxide synthase (NOS) inhibitor, l-nitroarginine methyl ester (l-NAME) is protective against the cytotoxicity of the vesicating agent bis (2-chloroethyl) sulphide (HD). Furthermore, these protective effects were not mediated through the inhibition of NOS. In studies designed to investigate the efficacy of additional arginine analogue NOS inhibitors as protective agents against this compound, l-thiocitrullline (l-TC) was identified as being extremely potent. In contrast to the protection conferred by l-NAME, however, l-TC was found to protect immature cultures of neurons against HD, as well as mature cultures. In addition, l-TC was found to exert its effects prophylactically, as opposed to the therapeutic characteristics of l-NAME. l-TC gave approximately 800% protection against HD with a one-h pretreatment compared to approximately 1500% protection with a 24-h pretreatment. The protection conferred by l-TC against HD was persistent, and did not require the continued presence of l-TC after the initial HD lesion was expressed. The protective characteristics of l-TC against HD are very different than those of l-NAME and suggest that these closely related arginine analogues act at as yet unidentified and different sites to exert their effects.
Detection and Identification Section, Defense Research Establishment Suffield, Medicine Hat, Alberta, T1A 8K6, Canada.
T W
TW
Sawyer
J R
JR
Hancock
P A
PA
D'Agostino
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002642:Chick Embryo; D002645:Chickens; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009151:Mustard Gas / Q000633:toxicity*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000931:Antidotes; D002619:Chemical Warfare Agents; D004791:Enzyme Inhibitors; C086715:thiocitrulline; D002956:Citrulline; D019001:Nitric Oxide Synthase; D013890:Thiourea; D009151:Mustard Gas; D019331:NG-Nitroarginine Methyl Ester