Mechanism of in vitro and in vivo inhibition of cholinesterase activity by diisopropyl fluorophosphate.

cholinergic effects of the fluorophosphates and those of physostigmine was noted by the British workers, McCombie et al.,’ and by Adrian and his group.2 The theory of chemical mediation of the transmission of nerve impulses through the autonomic nervous system identifies ac&ylcholine as the mediator. The presence of the enzyme, cholinesterase, at sites where acetylcholine is liberated by the nerve impulse leads to the rapid hydrolysis of acetylcholine. Since physostigmine decreases the activity of cholinesterase in vitro, it is presumed that the acetylcholine-like action of physostigmine is due to a similar enzyme inhibition in vivo, with resultant accumulation of acetylcholine. Because of the physiological similarity of diisopropyl fluorophosphate and physostigmine, Mackworthz studied the effect of incubating alkyl fluorophosphates with horse serum cholinesterase. He observed inactivation of the enzyme. The present work is concerned with a study of the mechanisms of the in vitro and in vivo inhibition of t,he cholinesterase qctivities of serum, red blood cells, and tissues in the rabbit, monkey, and man by diisopropyl fluorophosphate.