Inhibition of brain carboxylesterases by neurotoxic and nonneurotoxic organophosphorus compounds

Carboxylesterases (EC 3.1.1.1) of chicken brain were investigated by applying kinetic analysis of organophosphorus inhibition. By iterative elimination of exponential inhibition curves and by sequential inhibition experiments using a combination of two organophosphorus inhibitors, 11 different carboxylesterases of chicken brain were characterized with respect to their phenyl valerate-hydrolyzing activity (milliunits per gram of brain) and their inhibition by O,O-diethyl O-4-nitrophenyl phosphate (Paraoxon), O,O-diisopropylphosphorofluoridate, and N,N'-diisopropylphosphorodiamidic fluoride (Mipafox). The bimolecular inhibition rate constants (liters . mole-1 . min-1) were calculated for the 11 enzymes and 3 organophosphorus compounds. The corresponding data for acetylcholinesterase (EC 3.1.1.7) in chicken brain were determined. The importance of inhibition rate constants for the development of acute cholinergic symptoms, delayed neurotoxicity, and atypical organophosphate effects is shown.