532 ANNALS NEW YORK ACADEMY OF SCIENCES 



tion: vitamin K, ether, chloral, and some hormone preparations, such 

 as estrone, progestin, testosterone, etc.^^- ^^ Observations on these in- 

 hibitions are not yet detailed, and their exact significance is not yet 

 defined. It should be recognized that, in general, any enzyme is sub- 

 ject to in vitro inhibition by a great number of compounds, particularly 

 at relatively high concentration. Such inhibitions probably do re- 

 flect an interaction of the inhibitor with the enzyme molecule, but the 

 in vivo significance of such inhibitions is very often cjuestionable. 



There is evidence to indicate that the inhibitors which we have al- 

 ready described form reversible enzyme-inhibitor complexes. Matt- 

 hes," for example, first showed that dialysis of a mixture of cholin- 

 esterase and physostigmine resulted in the restoration of the enzyme 

 activity. Similarly, dilution of cholinesterase physostigmine mixtures 

 results in a relative increase of cholinesterase activity, presumably as 

 the result of the dissociation of the inactive enzyme-inhibitor com- 

 plgx.22, 26 Zeller has shown that the inhibition of cholinesterase by 

 pyrazolons and sulfonamides is similarly reversible, by dialysis of the 

 corresponding enzyme-inhibitor complexes. ^^ 



IN VITRO AND IN VIVO INHIBITION BY DIISOPROPYL- 

 FLUOROPHOSPHATE (DFP) 



We should now like to present a description of the properties of a 

 compound, typical of an entire group, which, in contrast to the inhibi- 

 tors we have described above, forms a combination with cholinesterase 

 which it has, so far, not been found possible to reverse. This com- 

 pound is diisopropyl-fluorophosphate. It is one of a group of alkyl 

 fluorophosphates first described by Lange and Krueger.^"* During the 

 war, it was regarded as a potential chemical warfare agent, and its 

 properties were first investigated by British workers. Adrian, Mc- 

 Combie, B. A. Kilby, and M. Kilby^^- ^"^ noted the similarity between 

 the cholinergic effects of the fluorophosphates and those of physostig- 

 mine. Mackworth" found that incubation of the alkyl fluorophos- 

 phates with horse serum cholinesterase resulted in the inactivation of 

 the enzyme, and that dialysis of the fluorophosphate-cholinesterase 

 mixture did not result in any restoration of cholinesterase activity. 

 Our interest in the mechanism of the anticholinesterase action was first 

 aroused when we noted that, upon exposure of men to very low concen- 

 trations of this agent, the serum cholinesterase was very markedly re- 

 duced to 2 to 5 per cent of the pre-exposure value, in spite of the fact 

 that there were only slight or doubtful systemic symptoms. The 



