Interaction of methamidophos with hen and human acetylcholinesterase and neuropathy target esterase

Abstract

Methamidophos causes acute cholinergic toxicity in several species, including man, and organophosphate-induced delayed polyneuropathy which has been reported in man but not in the hen. Acetylcholinesterase (AChE) and neuropathy target esterase (NTE) are thought to be the molecular targets of acute and delayed toxicity, respectively. The rate constants of inhibition (k_a) and reactivation (k₊₃) of human and hen brain AChE and NTE by methamidophos resolved optical isomers are here reported. NTE inhibition was progressive and irreversible. Human and hen NTE k_a (M⁻¹·m⁻¹) ford-(+) methamidophos was 88 and 59, respectively, and forl-(−) methamidophos 3.2 and 3.0, respectively. AChE spontaneously reactivates after inhibition.d-(+) methamidophos 10⁻³·k_a (M⁻¹·m⁻¹) for human and hen AChE was 0.24 and 0.13; 10³·k₊₃ (m⁻¹) was 0.83 and 0.69, respectively,l-(−) Methamidophos 10⁻³·k_a (M⁻¹·m⁻¹) for human and hen AChE was 5.7 and 2.8, whereas 10³ · k₊₃ (m⁻¹) was 6.50 and 1.52, respectively.l-(−)-Inhibited AChE reactivated to about 60% for human and 30% for hen enzymes, respectively.d-(+)-Inhibited AChE reactivated to about 10–20% for both species. Maximal reactivation occurred within 4–6 h when a plateau was reached. The larger and faster reactivation of human AChE inhibited in vitro byl-(−) methamidophos suggests that a corresponding effect might be possible in vivo and therefore explain, in part, the relatively higher susceptibility of man to delayed polyneuropathy induced by racemic methamidophos which occurs, however, with doses always causing severe cholinergic toxicity.