Reactivation and Aging of Neurotoxic Esterase Inhibited by a Variety of Organophosphorus Esters

1. It was proposed [Johnson (1974) J. Neurochem. 23, 785--789] that both inhibition of neurotoxic esterase of nervous tissue and subsequent 'aging' of the inhibited esterase are necessary events in the pathogenesis of organophosphate-induced delayed neuropathy: aging has now been demonstrated with a number of neurotoxic compounds. 2. Reactivation by KF was observed for hen brain neurotoxic esterase inhibited by 14 organophosphates and phosphonates, and time-dependent loss of reactivatibility (aging) occurred in every case. 3. For five other compounds no reactivation occurred and aging could not therefore be established, but independent evidence for two compounds suggests that aging was rapid. 4. Half-lives of aging of neurotoxic esterase inhibited by phosphates ranged from less than 1 min to 10 min, and for phosphonates the range was 3--600 min. 5. The relationship of these findings to the mechanism of toxicity and to the prospects of therapy are considered. 6. Aging occurred rapidly with aryloxy and linear alkoxy groups attached to phosphorus and slowly with a highly branched alkoxy substituent: these effects seem incompatible with an SN1 (dealkylation) mechanism.