Possible role of microtubules and associated proteases in organophosphorus ester-induced delayed neurotoxicity

Abstract

Organophosphorus delayed neurotoxicants (phenyl saligenin cyclic phosphate and diisopropyl phosphorofluoridate) altered cyclic AMP (cAMP)-dependent phosphorylation and several other processes in brain homogenates and cytoplasmic microtubules. Phenyl saligenin cyclic phosphate slightly stimulated in vitro cAMP-dependent phosphorylation in brain homogenates of three species (rat, mouse and rabbit) that have been reported to be insensitive to delayed neurotoxicity, whereas it slightly decreased this phosphorylation in brain homogenates of three sensitive species (chicken, cow and pig) and in brain microtubules of chicken and pig. The microtubule-associated processes that were moderately inhibited by phenyl saligenin cyclic phosphate in sensitive species were: in vitro [3H]cAMP binding to protein kinase, in vitro assembly when tubulin rings were absent, and cAMP-dependent phosphorylation of microtubule-associated proteins (MAPs) both in vitro and on intracerebral administration of 32Pi. The endogenous proteases that degrade the high molecular weight MAPs were strongly inhibited in vitro by phenyl saligenin cyclic phosphate and diisopropyl phosphorofluoridate. In contrast, treatment of chickens with diisopropyl phosphorofluoridate remarkably decreased the in vitro stability of their brain cytoplasmic high molecular weight MAPs, perhaps by enhancing the MAPs-degrading protease activity. These findings indicate that the MAPs-protease system is a possible target for organophosphorus delayed neurotoxicants.