The Impact of Pesticides - Academy Publish

compounds. Reaction 3, called “aging”, represents non-enzymatic time-dependentloss of one alkyl group (R) bound to the phosphorus. X stands for acyl radical (i.e.Cl¯, F¯, CN¯, p-nitrophenol etc.).AChE-OH + X-P(O)-(OR) 2(1)(3)-X - AChE-O-P(O)-(OR) 2+H 2 OAChE-O-P(O)(OR)(O - ) + ROH(2)The mechanism of OP poisoning involves inhibition of AChE at synapses andneuromuscular junctions in cholinergic pathways leading to accumulation ofacetylcholine and overstimulation of postsynaptic muscarinic and nicotinic receptors(Figure 1). Inhibition of AChE occurs after phosphorylation of hydroxyl group atserine at the active site of the enzyme. Following inhibition, AChE can bespontaneously reactivated at the rate that depends on chemical structure of OP. ForOP having dimethyl radicals the AChE reactivation is relatively rapid with a halftimeof about 1-2 hours, while that for OP having diethyl functional groups is 31-57hours. For OP belonging to the group of warfare nerve agents (soman, sarin, tabun,VX) having branched radicals spontaneous AChE reactivation does not occur at all.For certain OP, an additional step can occur on phosphorylated AChE known asaging reaction that represents non-enzymatic time-dependent loss of one alkyl group(R) bound to the phosphorus. The aging reaction depends on the chemical structureof the inhibitor and leads to a stable non-reactivatable form of phosphorylatedAChE (Reiner and Pleština, 1979; Worek and Diepold, 1999; Jokanović andStojiljković, 2006; Jokanović and Prostran, 2009).The duration of effects is determined mainly by the properties of the compound: itsliposolubility, the stability of the OP-AChE complex and whether it is reactivatableafter the use of cholinesterase reactivators (such as oximes). It is important to notethat only OP containing P=O bond (known as direct inhibitors) are potent AChEinhibitors; those having a P=S group (indirect inhibitors) must be metabolicallyactivated to P=O group (Jokanović, 2001). The signs and symptoms of poisoningwith direct inhibitors appear quickly during or after exposure, while those withindirect inhibitors appear slowly and last longer, even up to several days aftercessation of exposure.Clinical diagnosis of acute poisoning with OP compounds is relatively simple and isbased on medical history, circumstances of exposure, clinical presentation, andlaboratory tests. Confirmation of diagnosis can be made by measurement oferythrocyte AChE or plasma cholinesterase (ChE). Activities of these enzymes havebeen accepted as biomarkers of exposure and/or toxicity of OP. Erythrocyte AChEis identical to the enzyme present in the target synapses and its levels areassumed to reflect the effects in target organs. For that reason, erythrocyte AChE isregarded as biomarker of toxicity of these compounds. It is difficult to know, dueto pharmacokinetic reasons, how closely AChE inhibition in erythrocytes reflectsthat in the nervous system since access to blood is easier than access to brain. Thus,the inhibition of AChE in erythrocytes may be overestimated relative to that inbrain (Jokanović and Maksimović, 1997). In addition, AChE in brain is restored byde novo synthesis more rapidly than in erythrocytes where AChE activity isrecovered via erythropoesis. Inhibition of ChE does not provide accurateinformation related to clinical severity of the poisoning. Many OP insecticides (e.g.chlorpyrifos, demethon, malathion) appear to be more potent inhibitors of ChE thanthey are of erythrocyte AChE and, as the consequence, ChE inhibition might occurto a greater extent than AChE inhibition.AcademyPublish.org - The Impact of Pesticides41