The reversible inhibition of acetylesterase by diisopropyl fluorophosphate and tetraethyl pyrophosphate.

Diisopropyl fluorophosphate (DFP) has been shown to be a remarkably potent inhibitor of the enzymatic hydrolysis of acetylcholine (1). As a result of a wide survey (2), inhibition by dialkyl fluorophosphates appears to be specific for certain esterases and lipases (kidney acid phosphatase was found to be inhibited by relatively high concentrations). Since the cholinesterase of mammalian brain and nerve tissue is narrowly specific for acetylcholine and acetyl-@methylcholine (3), it is often called “true” cholinesterase. Other esterases of wider specificity (those hydrolyzing tributyrin, for example) also hydrolyze acetylcholine, but are frequently referred to as “pseudo” cholinesterases. While studying the inhibition of cholinesterase by DFP in vitro and in z&o, Mazur and Bodansky (4) found that different tissue cholinesterases show differing degrees of sensitivity to DFP. These results have been interpreted by Hawkins and Mendel (5) and by us (6) as indicating that pseudocholinesterase is about 100 times as sensitive to the inhibitory action of DFP as is cholinesterase. From a correlation of toxicity with inhibition of brain cholinesterase, Nachmansohn and Feld (7) have concluded that the toxicity of DFP is very probably due to its action on “true” cholinesterase. Since dialysis or dilution of cholinesterase-DFP mixtures or of tissue cholinesterase from animals poisoned with DFP did not result in any increase in cholinesterase, the DFP inhibition of brain cholinesterase is not to be considered readily reversible (4). However, Nachmansohn et cd. (8) have found that over a relatively short period of time the inhibition by DFP can be reversed by dilution, the extent of the reversal being dependent on temperature, time, and DFP concentration. Eserine, which inhibits cholinesterase reversibly, was found to protect the enzyme against irreversible DFP inhibition (9). Mazur (10) also demonstrated an enzyme in animal tissues capable of hydrolyzing the phosphorus-fluorine bond of alkyl fluorophosphates, so that there exists in vivo concurrent inhibition of cholinesterase and detoxification. Hexaethyl tetraphosphate (HETP) exerts a