Cresylbenzodioxaphosphorin oxide pretreatment alters soman-induced toxicity and inhibition of tissue cholinesterase activity of the rat.
The toxicity of soman was investigated in the rat with and without pretreatment with cresylbenzodioxaphosphorin oxide (CBDP). Without pretreatment, the 24-h LD50 for soman was 118.2 micrograms/kg s.c., and soman inhibited carboxylesterase (CaE) activity in plasma (ED50 of 55 micrograms/kg) and cholinesterase (ChE) activity in brain regions (ED50 values of 65-105 micrograms/kg) in a dose-related manner. With pretreatment, the 24-h LD50 for soman was reduced by approximately 6-fold and 8-fold (by 1.0 mg/kg and 16.0 mg/kg of CBDP, respectively), and the ED50 values for soman-induced inhibition of ChE activity in brain regions were reduced by approximately 10-fold (by 1.0 mg/kg of CBDP). The dose-dependent severity of soman intoxication varied widely in rats treated with soman alone but not in CBDP-pretreated rats, and the ED50 for the occurrence of signs of soman intoxication was reduced approximately 7-fold following CBDP (1.0 mg/kg) pretreatment. These data support the hypothesis that CBDP pretreatment effectively blocks tissue CaE sites which serve to detoxify soman, thus potentiating both the soman-induced inhibition of ChE in the CNS and the lethality of soman.
Jimmerson
V R
VR
Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Shih
T M
TM
Maxwell
D M
DM
Mailman
R B
RB
D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors; D004357:Drug Synergism; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008297:Male; D009943:Organophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D012999:Soman; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase