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.