Phenylmethylsulfonyl Fluoride,a Potentiator of Neuropathy,Alters the Interaction of Organophosphorus Compounds with SolubleBrain Esterases.

Phenylmethylsulfonyl fluoride (PMSF) is a protease andesteraseinhibitor that causes protection or potentiation/promotion of organophosphorusdelayed neuropathy (OPIDN) depending on whether it is dosed beforeor after an inducer of delayed neuropathy. The molecular target ofpromotion has not yet been identified. Kinetic data of esterase inhibitionwere first obtained for PMSF with a soluble chicken brain fractionand then analyzed using a kinetic model with a multienzymatic systemin which inhibition occurred with the simultaneous chemical hydrolysisof the inhibitor and ongoing inhibition (inhibition during the substratereaction). The best fitting model was a model with resistant fraction,Eα (28%), and two sensitive enzymatic entities, Eβ (61%)and Eγ (11%), with I50at 20 min of 70 and 447 μM,respectively. The estimated constant of the chemical hydrolysis ofPMSF was kh= 0.23 min–1. Eα,which is sensitive to mipafox and resistant to PMSF, became less sensitiveto mipafox when the preparation was preincubated with PMSF. Its EαI50(30 min) of mipafox increased with the PMSF concentrationused to preincubate it. Eγ is sensitive to both PMSF and mipafox,and after preincubation with PMSF, Eγ became less sensitiveto mipafox and was totally resistant after preincubation with 10 μMPMSF or more. The sensitivity of Eα to paraoxon (I5030 min from 9 to 11 nM) diminished after PMSF preincubation (I5030 min 185 nM) and showed no spontaneous reactivation capacity.The nature of these interactions is unknown but might be due to covalentbinding at sites other than the substrate catalytic center. Such interactionsshould be considered to interpret the potentiation/promotion phenomenonof PMSF and to understand the effects of multiple exposures to chemicals. [ABSTRACT FROM AUTHOR]