Kinetics of the postinhibitory reactions of acetylcholinesterase poisoned by chiral isomalathion: a surprising nonreactivation induced by the RP stereoisomers.
Inhibitory (ki), spontaneous (k0), and oxime-mediated reactivation (k(oxime)) reaction kinetics for the four stereoisomers of isomalathion (SPRC,SPSC,RPRC, and RPSC) were determined against rat brain acetylcholinesterase (AChE). (SPRC)-Isomalathion was the most potent anticholinesterase agent and RPSC-isomalathion the least potent with racemic material approximately midway in activity. Following inhibition of rat brain AChE by (SPRC)- or (SPSC)-isomalathion, k0 and k(oxime) values were obtained that were comparable to (SP)-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 (RPSC)- or (RPRC)-isomalathion. This observation was not consistent with (RP)-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 (RP)-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.
Berkman
C E
CE
Department of Chemistry, Loyola University of Chicago, Illinois 60626.
Ryu
S
S
Quinn
D A
DA
Thompson
C M
CM
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D007700:Kinetics; D008294:Malathion / Q000494:pharmacology*; D008743:Methyl Parathion / Q000031:analogs & derivatives / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D011220:Pralidoxime Compounds / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011220:Pralidoxime Compounds; D008743:Methyl Parathion; C072329:S-methyl-methylparathion; C018326:isomalathion; D000110:Acetylcholinesterase; C028797:pralidoxime; D008294:Malathion