Studies on Cholinesterase Iv. on the Mechanism of Diisopropyl Fluorophosphate Action in Vivo*

There is growing evidence for the assumption that the profound biological effects produced by some compounds in low concentrations may be attributed to an interaction with enzymes. This is true for certain cell constituents as well as for toxic compounds not existing normally in the body. Several vitamins have been found to be prosthetic groups of enzymes and for a number of drugs it could be demonstrated that the effect has to be attributed to their action on either the protein or non-protein moiety of an enzyme system. When it became necessary to study certain toxic compounds considered as potential agents in chemical warfare, English investigators, as stressed by Pet.ers and his associates (1) and Dixon and Needham (Z), approached the problem based on the assumption that a probable explanation for the mode of action may be the effect of these compounds on enzymes. According to Dixon and Needham, the most powerful and most specific enzyme inhibitor known is the diisopropyl fluorophosphate (DFP). This compound may inhibit cholinesterase in concentrations as low as 1 X lO+O M. I1lthough twenty enzyme systems were studied, none of them was affected except the esterases. The toxic symptoms in animals exposed to DFP indicate that the central nervous system is affected. It is known that all nervous tissue contains cholinesterase in high concentrations (3, 4). Much evidence has accumulated in support of the paramount importance of this enzyme for nerve conduction (5-8). The discovery of DFP offered an unusual tool to test this assumption. This compound inactivates cholinesterase irreversibly. This irreversible inactivation is, however, not an immediate process, as was first believed, but requires a certain period of time (9, 10). Owing to this peculiar feature of this compound, a striking parallelism has been established in nerves exposed to DFP between the progressive irreversible inactivation of cholinesterase and the abolition of conduction. In view of all these facts and since abolition of conduction is