Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase

Organophosphorus compounds (OP) are in wide spread use as pesticides and highly toxic OP may he used as chemical warfare agents (nerve agents). OP inhibit acetycholinesterase (AChE). therefore. standard treatment includes AChE reactivators (oximes) in combination with antimuscarinic agents. In the last decades. the efficacy of oximes has been investigated in various animal models. mostly in rodents. However, extrapolating animal data to humans is problematical because of marked differences between rodents and humans concerning the toxicokinetics of nerve agents, the pharmacokinetics of antidotes and the AChE enzyme kinetics. In order to improve the understanding of species differences and to enable a more reliable extrapolation of animal data to humans a study was initiated to investigate the effect of highly toxic nerve agents. i.e. VX. Russian VX (VR) and Chinese VX (CVX). with human and pig erythrocyte AChE. Hereby, the rate constants for the inhibition of AChE by these OP (k(i)) and for the spontaneous dealkylation (k(a)) and reactivation (k(s)) of OP-inhibited AChE as well as for the oxime-induced reactivation of OP-inhibited AChE by the oximes obidoxime, 2-PAM, HI 6, HLo 7 and MMB-4 were determined. Compared to human AChE pig AChE showed a lower sensitivity towards the investigated OP. Furthermore. a slower spontaneous dealkylation and reactivation of pig AChE was recorded. The potency of the investigated oximes was remarkably lower with OP-inhibited pig, AChE. These data may contribute a better understanding of species differences and may provide a kinetic basis for extrapolation of data front pig experiments to humans. (c) 2006 Elsevier Ireland Ltd. All rights reserved.