Rates of spontaneous reactivation and aging of acetyicholinesterase in human erythrocytes after inhibition by organophosphorus pesticides

Abstract

<jats:p> The in vitro rates of spontaneous reactivation and aging in human erythrocyte acetylcholinesterase were studied after inhibition by a dimethoxy (RjR<jats:sub>2</jats:sub>) and diethoxy substituted (RjR<jats:sub>2</jats:sub>) organophosphate pesticide (OP) of general structure R<jats:sub>1</jats:sub>R<jats:sub>2</jats:sub>P(O)X. These have been compared with data for human plasma cholinesterase previously reported using a similar methodology. </jats:p><jats:p> A significantly slower rate of aging for erythrocyte acetylcholinesterase was found compared to plasma cholinesterase, whether inhibited by dimethoxy or diethoxy substituted OPs. For diethoxy OPs the rate of spontaneous reactivation of the inhibited plasma enzyme was significantly slower than for the inhibited red cell enzyme. This acetylcholinesterase, and previously published plasma cholinesterase, data suggest that in practise a blood sample taken 30-40 h after significant acute OP exposure will still show inhibition in either plasma or erythrocyte cholinesterase when analysed, but that any inhibited plasma enzyme is more likely to be in the aged form. In contrast a substantial proportion of the erythrocyte acetylcholinesterase is found unaged and therefore sensitive to reactivation by oximes. Samples from an occupational exposure where depressions in plasma or erythrocyte cholinesterase activity from baseline measurements were reactivated ex vivo using the oxime 2-PAM support this hypothesis. These data also confirm that the plasma enzyme is a more sensitive than erythrocyte acetylcholinesterase as an indicator of OP exposure and thus the potential value of ex vivo oxime reactivation of erythrocyte acetylcholinesterase in a blood sample to indicate subclinical OP exposure may be limited. However, this study is too small to draw conclusions on the sensitivity of ex vivo oxime reactivation of acetylcholinesterase as a novel biomarker of excessive OP absorption. Given that there is a better relationship between anticholinergic symptoms and red cell acetylcholinesterase inhibition, and that the slower resynthesis rate of any aged or inhibited red cell enzyme may be interpretatively useful when venepuncture is delayed, it is suggested that red cell acetylcholinesterase activity does have a place in monitoring potential OP exposure. </jats:p>

Pyridinium Oximes as Cholinesterase Reactivators. Structure-Activity Relationship and Efficacy in the Treatment of Poisoning with Organophosphorus Compounds

“…HI-6 is an effective antidote against toxic fluorophosphonates, especially soman, while TMB-4 and LüH-6 are effective in the treatment of acute poisoning with OP insecticides. TMB-4 and LüH-6 are more effective oximes for the treatment of acute tabun poisonings than HI-6, but their potency to eliminate tabun-induced acute lethal effects is relatively low when administered at low human-relevant doses [11,45,54,55].…”

“…The half-time for aging of the tabun-AChE complex is about 46 hours [6,7,8]. For OP pesticides containing dimethyl phosphate groups the halftime of spontaneous reactivation of phosphorylated AChE in vitro is about 1 hour and the half-time of aging is 3.7 hours, while these for diethyl phosphates are slower being about 31-57 hours and 31 hours, respectively [5,10,11].…”

Effect of Diplodiatoxin (Stenocarpella maydis) on Some Enzymatic Profiles in Male and Female Rats

“…The level of AChE is an excellent indicator of its e!ect on nerve synapses (Vandekar, 1980). AChE is a key enzyme in the metabolism of the neurotransmitter acetylcholine (ACh) within the cholinergic nervous system (Mason et al, 2000). Sexual dimorphism, reversal of toxicity, and correlation between serum and liver have been studied.…”

Analytical approaches to investigate protein–pesticide adducts

“…potential, and DFP also exploits the relative resistance to hydrolysis of a diisopropoxy adduct [27][28][29][30]. We have used 3 H-DFP binding to tissue homogenates to quantitate the level of active serine hydrolases, and also a means to visualise protein targets by autoradiography.…”