The role of carboxylesterase in species variation of oxime protection against soman.
Oxime protection against soman, a highly toxic anticholinesterase agent, was examined in mice and guinea pigs. The maximal protection produced by the oximes PAM and HI-6 varied as much as 6-fold between these species. Since endogenous carboxylesterase (CaE) is known to be an important determinant of species variation in soman toxicity, the protection of PAM and HI-6 against soman was also measured in animals whose endogenous CaE was inhibited with cresylbenzodioxaphosphorin oxide. In CaE-inhibited animals the soman LD50 values were similar in unprotected mice and guinea pigs (10.2 vs. 12.2 micrograms/kg) and oxime-protected mice and guinea pigs (38.1 vs. 40.3 micrograms/kg for PAM; 159 vs. 151 micrograms/kg for HI-6). The levels of oxime protection observed in CaE-inhibited animals agreed with previous experiments in other species that have no endogenous plasma CaE. The 4-5 times greater in vivo protection against soman of HI-6 vs. PAM in CaE-inhibited animals correlated with in vitro experiments in which HI-6 produced 3-5 times more oxime reactivation of soman-inhibited AChE than PAM.
Maxwell
D M
DM
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Brecht
K M
KM
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000502:physiology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010091:Oximes / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013045:Species Specificity
D002801:Cholinesterase Reactivators; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; D002265:Carboxylic Ester Hydrolases; C022870:asoxime chloride