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 (ka) 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 ka (M-1.m-1) for D-(+) methamidophos was 88 and 59, respectively, and for L-(-) methamidophos 3.2 and 3.0, respectively. AChE spontaneously reactivates after inhibition. D-(+) methamidophos 10(-3).ka (M-1.m-1) for human and hen AChE was 0.24 and 0.13; 10(3).k+3 (m-1) was 0.83 and 0.69, respectively. L-(-) Methamidophos 10(-3).ka (M-1.m-1) for human and hen AChE was 5.7 and 2.8, whereas 10(3).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 by L-(-) 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.

The relationship between isofenphos cholinergic toxicity and the development of polyneuropathy in hens and humans

“…Clinical observation of cases of OP poisoning and biochemical information in humans are consistent with these hen data (Lotti and Johnson 1978). One exception, in this respect, is methamidophos (O, S-dimethyl phosphoroamidothioate), which has a similar low ratio with both hen and human enzymes but the cholinergic syndrome preceding OPIDP is less severe in man than in hens (Bertolazzi et al 1991). The explanation for this is the higher rate of spontaneous reactivation of AChE in humans, making survival from methamidophos poisoning easier in humans than in hens.…”

Histologic Peripheral Nerve Changes in Rats Induced by Deltamethrin

“…In the classic work of Cavanagh (1954) in intoxications with TOCP, besides peripheral nerve damage, changes in the anterior horn cells and lateral corticospinal tracts were described. These lesions are believed to be associated with inhibition of the so-called &&neuropathic target esterase'' (Johnson, 1982;Lotti et al, 1984;Bertolazzi et al, 1991) that su!er a process of &&aging.'' This results in a distal axonopathy of long and large-diameter axons of the spinal cord and peripheral nerves (dying-back neuropathy) which occurs several days or weeks after exposure.…”

GABA and Dopamine Release from Different Brain Regions in Mice with Chronic Exposure to Organophosphate Methamidophos

“…Agent-induced ACh accumulation generates side effects that involve action on other CNS neurotransmitter systems (e.g., norepinephrine, dopamine, and γ-amino butyric acid). The interplay of various neurotransmitters within the nervous system probably results in these varied side effects 15 , although nerve agents may exert direct effects on these same noncholinergic systems 16 .…”