Soman and sarin inhibition of molecular forms of acetylcholinesterase in mice. Time course of recovery and reactivation by the oxime HI-6.
The in vivo sensitivity of the molecular forms of the enzyme acetylcholinesterase to inhibition by either soman or sarin, reactivation by HI-6 and the time course of recovery following inhibition by soman were investigated in mice. Administration of HI-6 (50 mg/kg, i.p.) immediately after soman (100 micrograms/kg, s.c.) or sarin (150 micrograms/kg, s.c.) resulted in an apparent selective reactivation of the 10S and 16S molecular forms of acetylcholinesterase and no reactivation of the 4S form of diaphragm acetylcholinesterase. The apparent selectivity of the reactivation of the molecular forms of the acetylcholinesterase was probably due to the fact that the 10S and 16S forms of acetylcholinesterase are located primarily extracellularly and the 4S form intracellularly. The HI-6 was restricted primarily to the extracellular compartment due to its quaternary, hydrophilic nature. If the administration of HI-6 was delayed until 60 min following soman (100 micrograms/kg, s.c.) injection, no reactivation of any of the molecular forms of acetylcholinesterase could be found in the diaphragm. The soman-inhibited acetylcholinesterase had probably aged and, thus, was not susceptible to reactivation by HI-6. The time course of recovery of the molecular forms in the diaphragm occurred rather quickly with the smaller 4S and 10S forms recovering to control levels faster than the larger 16S form. It took between 8 and 16 days for the 16S form to recover to normal. In the brain, hypothalamic acetylcholinesterase molecular forms such as the 4S recovered faster than the 10S form which had not recovered to control 16 days after soman administration; the 16S form of acetylcholinesterase was not detected in the brain.
Clement
J G
JG
Biomedical Defence Section, Defence Research Establishment Suffield, Ralston, Alberta, Canada.
Rosario
S
S
Bessette
E
E
Erhardt
N
N
D000110:Acetylcholinesterase; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D010091:Oximes; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012524:Sarin / Q000008:administration & dosage / Q000633:toxicity*; D012999:Soman / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D007527:Isoenzymes; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; C022870:asoxime chloride