Effect of endogenous carboxylesterase on HI-6 protection against soman toxicity.
Species variation in oxime protection against soman was examined in mice and guinea pigs with the bis-pyridinium oxime HI-6. HI-6, an effective reactivator of soman-inhibited acetylcholinesterase, produced greater maximal protection against soman in mice than in guinea pigs, although there was no species difference in acetylcholinesterase reactivation. In mice the maximal therapeutic dose of HI-6 increased the LD50 of soman from 113 micrograms/kg in unprotected animals to 992 micrograms/kg in animals receiving 76.6 mg/kg of HI-6 and 11.2 mg/kg of atropine. In guinea pigs the maximal therapeutic dose of HI-6 increased the LD50 of soman from 28.2 micrograms/kg in unprotected animals to 179 micrograms/kg in animals receiving 136 mg/kg of HI-6 and 16 mg/kg of atropine. In animals whose carboxylesterase had been inhibited with 2 mg/kg of cresylbenzodioxaphosphorin oxide, the soman LD50 values in unprotected mice and guinea pigs were similar (10.2 vs. 12.2 micrograms/kg), as were the soman LD50 values in mice and guinea pigs protected with HI-6 and atropine (159 vs. 151 micrograms/kg). In cresylbenzodioxaphosphorin oxide-treated mice and guinea pigs the achievement of equal HI-6 protection against soman correlated with the ability of HI-6 to produce equal levels of reactivation of soman-inhibited acetylcholinesterase in both species. In animals whose carboxylesterase levels were different, the animals with higher carboxylesterase levels (i.e., mice) achieved higher levels of HI-6 protection against soman than did animals with lower levels of carboxylesterase (i.e, guinea pigs). This observation suggested that, in addition to its reactivation of soman-inhibited acetylcholinesterase, HI-6 produced an effect on carboxylesterase that increased its therapeutic effect in mice.
Maxwell
D M
DM
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.
Koplovitz
I
I
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use*; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010091:Oximes; D011726:Pyridinium Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012999:Soman / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D013045:Species Specificity
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C022870:asoxime chloride