KINETICS OF THE POSTINHIBITORY REACTIONS OF ACETYLCHOLINESTERASE POISONED BY CHIRAL ISOMALATHION - A SURPRISING NONREACTIVATION INDUCED BY THE RP STEREOISOMERS

Inhibitory (k(i)), spontaneous (k0), and oxime-mediated reactivation (k(oxime)) reaction kinetics for the four stereoisomers of isomalathion (S(P)R(C), S(P)S(C), R(P)R(C), and R(P)S(C)) were determined against rat brain acetylcholinesterase (AChE). (S(P)R(C))-Isomalathion was the most potent anticholinesterase agent and R(P)S(C)-isomalathion the least potent with racemic material approximately midway in activity. Following inhibition of rat brain AChE by (S(P)R(C))- or (S(P)S(C))-isomalathion, k0 and k(oxime) values were obtained that were comparable to (S(P))-isoparathion methyl, indicating that the same mechanism of inhibition was shared, namely, formation of an O,S-dimethyl phosphorothiolated enzyme. Conversely, no appreciable reactivation occurred with or without oxime following inhibition of rat brain AChE by (R(P)S(C))-or(R(P)R(C))-isomalathion. This observation was not consistent with (R(P))-isoparathion methyl, and a switch in inhibition mechanism to the loss of the thiomethyl moiety is suggested. The nonreactivation of rat brain AChE following inhibition by the (R(P))-isomalathion stereoisomers is postulated to result from a mechanism involving either a beta-elimination of diethyl fumarate or displacement of the thiosuccinate moiety from the phosphate moiety.