Reactivation of organophosphorus - Inhibited human erythrocyte-acetylcholinesterase by oximes in vitro

Until now the efficacy of new antidotes against organophosphorus poisoning has been primarily evaluated in animal models. However, the transmission of these results to humans is hampered by species differences. Besides atropine, oximes are considered as main antidotes. The most important effect of these compounds is the reactivation of inhibited acetylcholinesterase (AChE). The reactivating potency of oximes can be investigated with human material in vitro and was evaluated in the present study with human erythrocyte AChE after inhibition by different nerve agents and pesticides. Isolated human erythrocyte AChE was inhibited by organophosphorus compounds, then the inhibitor removed in part of the experiments, the inhibited enzyme reactivated by obidoxime, pralidoxime, HI-6 or HLo 7 (10 - 100 mu M) and the AChE activity determined photometrically according to Ellman. The reactivation of inhibited AChE by oximes was dependent on the organophosphate used. After soman, sarin, cyclosarin or VX the reactivation increased in the order HLo 7 > HI-6 > obidoxime > pralidoxime. Only obidoxime and HLo 7 reactivated tabun inhibited AChE partially, while pralidoxime and HI-6 were almost completely ineffective. The reactivation of pesticide inhibited AChE (20 compounds from 8 organophosphate classes) increased in the order: obidoxime > HLo 7 > pralidoxime > HI 6. Pralidoxime and HI-6 were only effective against methamidophos inhibited enzyme. These data indicate that the dioxime HLo 7 may be considered as a broad-spectrum antidote at human relevant doses. Obidoxime and HI-6 reactivate only pesticides and nerve agents respectively, and pralidoxime was the least effective oxime.