Irreversible phosphorylation of brain neurotoxic esterase. The primary event leading to the delayed neuropathy caused by some organophosphorus esters

Abstract

Organophosphorus compounds which cause delayed neurotoxic effects phosphorylate a characteristic nervous-tissue protein and inhibit its activity as an esterase. Studies with a variety of inhibitors reveal that the toxic effect does not occur because of the loss of esterase activity but depends on the chemistry of the inhibited enzyme. A process analogous to the 'aging' of inhibited cholinesterase occurs after neurotoxic esterase has been inhibited by neurotoxic agents which leaves a charged acidic group attached to the membrane-bound esterase. This charge could disrupt normal metabolism in the neurone. Protective compounds inhibit neurotoxic esterase but the 'aging' process cannot occur, so that there is no formation of a charged group. Neurotoxic esterase occurs widely in the brain. Attempts are being made to locate the enzyme intraneuronally. The present understanding is of great value in toxicology. However, it has not yet clarified the physiological processes which maintain long axons in normal health.