INTERACTION OF ORGANOPHOSPHORUS COMPOUNDS WITH CARBOXYLESTERASES IN THE RAT

Carboxylesterases (CarbE) are involved in detoxication of organophosph orus compounds (OPC) through two mechanisms: hydrolysis of ester bonds in OPC which contain them and binding of OPC at the active site of Ca rbE which reduces the amount of OPC available for acetylcholinesterase inhibition. This study of the interaction of rat plasma and liver Car bE with dichlorvos, soman and sarin in vitro and in vivo was undertake n in order to contribute to better understanding of the role of CarbE in detoxication of OPC. The results obtained have shown that inhibitor y potency (I-50) of dichlorvos, sarin and soman towards rat liver Carb E was 0.2 mu M, 0.5 mu M and 4.5 mu M, respectively, for 20-min incuba tion at 25 degrees C. Second-order rate constants (k(a)) for liver Car bE inhibition were 2.3 x 10(5) M(-1) min(-1), 6.9 x 10(4) M(-1) min(-1 ) and 1.1 x 10(4) M(-1) min(-1) for dichlorvos, sarin and soman, respe ctively. The corresponding values for plasma CarbE could not be calcul ated because of dominant spontaneous reactivation of inhibited CarbE. CarbE inhibited with these OPC in vitro spontaneously reactivate with half-times of 18, 143 and 497 min for sarin, dichlorvos and soman in p lasma and 111, 163 and 297 mill for sarin, soman and dichlorvos in liv er, respectively. These results were also confirmed in experiments in vivo in which rats were subcutaneously treated with 0.5 LD(50) of thes e agents. The half-times of spontaneous reactivation of rat plasma Car bE in vivo were 1.2, 2.0 and 2.7 h for dichlorvos, sarin and soman, re spectively. These findings have changed current understanding of the m echanism of interaction of CarbE with OPC and involvement of the enzym es in detoxication of OPC, suggesting an active and important role of the enzymes in metabolic conversions of OPC to their less toxic metabo lites.