Interaction of organophosphorus compounds with carboxylesterases in the rat

Abstract

Carboxylesterases (CarbE) are involved in detoxication of organophosphorus compounds (OPC) through two mechanisms: hydrolysis of ester bonds in OPC which contain them and binding of OPC at the active site of CarbE which reduces the amount of OPC available for acetylcholinesterase inhibition. This study of the interaction of rat plasma and liver CarbE with dichlorvos, soman and sarin in vitro and in vivo was undertaken in order to contribute to better understanding of the role of CarbE in detoxication of OPC. The results obtained have shown that inhibitory potency (I50) of dichlorvos, sarin and soman towards rat liver CarbE was 0.2 microM, 0.5 microM and 4.5 microM, respectively, for 20-min incubation at 25 degrees C. Second-order rate constants (k(a)) for liver CarbE 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, respectively. The corresponding values for plasma CarbE could not be calculated 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 plasma and 111, 163 and 297 min for sarin, soman and dichlorvos in liver, respectively. These results were also confirmed in experiments in vivo in which rats were subcutaneously treated with 0.5 LD50 of these agents. The half-times of spontaneous reactivation of rat plasma CarbE in vivo were 1.2, 2.0 and 2.7 h for dichlorvos, sarin and soman, respectively. These findings have changed current understanding of the mechanism of interaction of CarbE with OPC and involvement of the enzymes in detoxication of OPC, suggesting an active and important role of the enzymes in metabolic conversions of OPC to their less toxic metabolites.

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

“…Chemicals that provoke induction of the enzymes involved in activation of OPCs can make them more toxic, as well as the chemicals that inhibit enzymes included in the detoxification phase and vice versa. 40,[42][43][44] However, clinical impact of interactions due to inhibition/induction of enzymes involved in detoxification or activation is difficult to predict because they often produce effects on several enzyme systems.…”

Acetylcholinesterase activity in Corbicula fluminea Mull., as a biomarker of organophosphate pesticide pollution in Pinacanauan River, Philippines

“…Escartin and Porte (1997) had demonstrated that the gland possesses not only cholinesterase but also carboxylesterases, which can remove significant amounts of activated metabolites from parent organophosphate compounds, thus preventing them from reaching the main target AChE. These esterases hydrolyze a wide range of xenobiotic compounds and are believed to play a role in detoxification and tolerance for some OP pesticides (Maxwell 1992;Parkinson 1996), providing protection against neurotoxic compound poisoning (Gupta et al 1985;Jokanovic et al 1996;Parkinson 1996;Escartin and Porte 1997).…”

Biotransformation of Warfare Nerve Agents

“…In addition, because of the reversibility of the binding reaction of sarin and soman to CarbE, it appears that CarbE are involved in metabolic detoxification of these agents to their corresponding nontoxic metabolites IMPA and PMPA (Jokanović et al, 1996;Jokanović, 2009). Important proof supporting the significance of detoxification reactions of WNA in the body was presented by Fonnum and Sterri (1981), who reported that only 5% of LD 50 of soman in rats, or approximately 5 μg/kg, reacts with AChE and causes acute toxic effects, whereas the remaining 95% passes through various metabolic reactions.…”