Mechanisms of toxicity and tolerance to diisopropylphosphorofluoridate at the neuromuscular junction of the rat.
Diisopropylphosphorofluoridate (DFP), an irreversible inhibitor of acetylcholinesterase (AChE) activity, when given as an acute dose (1.5 mg/kg, sc) caused fasciculations and induced necrosis in rat skeletal muscle fibers. No adaptation was seen to daily dosing of DFP (1.5 mg/kg, sc) since all rats died after the second or third injection. Daily dosing of DFP in a concentration (0.5 mg/kg, sc) that as a single dose did not cause symptoms, produced onset of fasciculations on the third day associated with a reduced number of muscle fiber lesions. Further administration of DFP (14 days) caused disappearance of fasciculations and loss of sensitivity to the necrotizing actions in all muscles tested (diaphragm, soleus, and extensor digitorum longus). Activity of all molecular forms of AChE was reduced to 20-24% of control when symptoms of cholinergic hyperactivity appeared. Continuous injections of DFP (0.5 mg/kg/day, sc) up to 14 days did not cause greater inhibition of AChE activity. Instead, recovery of enzyme activity, especially of the 4S and 10S forms, was seen. During this period choline acetyltransferase activity (ChAT) was increased in muscle (intramuscular nerves) while the postsynaptic nicotinic acetylcholine receptor (nAChR) density (Bmax) was decreased to 44% without a change in the affinity constant (KD). It is concluded that neuromuscular adaptation to DFP is caused by recovery of AChE activity due to de novo synthesis and reduction in the number of nAChR.
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors; D004361:Drug Tolerance; D007531:Isoflurophate / Q000633:toxicity*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D009469:Neuromuscular Junction / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains
D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase