It is generally accepted that inhibition of
acetylcholinesterase (AChE) is the most important acute
toxic action of
organophosphorus compounds, leading to accumulation of
acetylcholine followed by a dysfunction of
cholinergic signaling. However, the degree of AChE inhibition is not uniformly correlated with
cholinergic dysfunction, probably because the excess of essential AChE varies among tissues. Moreover, the
cholinergic system shows remarkable plasticity, allowing modulations to compensate for dysfunctions of the canonical pathway. A prominent example is the living (-/-) AChE knockout mouse. Clinical experience indicates that precipitous inhibition of AChE leads to more severe
poisoning than more protracted yet finally complete inhibition. The former situation is seen in
parathion, the latter in
oxydemeton methyl poisoning. At first glance, this dichotomy is surprising since
parathion is a pro-
poison and has to be activated to the oxon, while the latter is still the ultimate inhibitor. Also
oxime therapy in
organophosphorus poisoning apparently gives perplexing results:
Oximes are usually able to reactivate diethylphosphorylated AChE, but the efficiency may be occasionally markedly smaller than expected from kinetic data. Dimethylphosphorylated AChE is in general less amenable to
oxime therapy, which largely fails in some cases of
dimethoate poisoning where aging was much faster than expected from a dimethylphosphorylated
enzyme. Similarly,
poisoning by
profenofos, an O,S-dialkyl
phosphate, leads to a rapidly aged
enzyme. Most surprisingly, these patients were usually well on admission, yet their erythrocyte AChE was completely inhibited. Analysis of the kinetic constants of the most important reaction pathways, determination of the reactant concentrations in vivo and comparison with computer simulations may reveal unexpected toxic reactions. Pertinent examples will be presented and the potentially underlying phenomena discussed.