Insecticides, acetylcholinesterase

Methomyl exerts toxicity by inhibiting acetylcholinesterase. As with other carbamate insecticides, acetylcholinesterase inhibition is much less persistent than with organophosphate intoxication. 

Mode of Action. All of the insecticidal carbamates are cholinergic, and poisoned insects and mammals exhibit violent convulsions and other neuromuscular disturbances. The insecticides are strong carbamylating inhibitors of acetylcholinesterase and may also have a direct action on the acetylcholine receptors because of their pronounced stmctural resemblance to acetylcholine. The overall mechanism for carbamate interaction with acetylcholinesterase is analogous to the normal three-step hydrolysis of acetylcholine however, is much slower than with the acetylated enzyme. 

Arthun DA, Chakraborti TK, Chapman JL, et al. 1991. Comparison of in vivo acetylcholinesterase (AChE) inhibition in neonatal and adult rats by three organophosphoms insecticides. Neurotoxicology 12 143. 

Hahn T, Ruhnke M, Luppa H. 1991. Inhibition of acetylcholinesterase and butyrylcholinesterase by the organophosphorus insecticide methyl parathion in the central nervous system of the golden hamster i Mesocricetus aumtus). Acta Histochem (Jena) 91 13-19. 

This process of aging is believed to be critical in the development of delayed neuropathy, after NTE has been phosphorylated by an OP (see Chapter 10, Section 10.2.4). It is believed that most, if not all, of the B-esterases are sensitive to inhibition by OPs because they, too, have reactive serine at their active sites. It is important to emphasize that the interaction shown in Fignre 2.11 occurs with OPs that contain an oxon group. Phosphorothionates, which contain instead a thion group, do not readily interact in this way. Many OP insecticides are phosphorothionates, but these need to be converted to phosphate (oxon) forms by oxidative desulfuration before inhibition of acetylcholinesterase can proceed to any significant extent (see Section 2.3.2.2). 

Mechanism of action can be an important factor determining selectivity. In the extreme case, one group of organisms has a site of action that is not present in another group. Thus, most of the insecticides that are neurotoxic have very little phytotoxicity indeed, some of them (e.g., the OPs dimethoate, disyston, and demeton-5 -methyl) are good systemic insecticides. Most herbicides that act upon photosynthesis (e.g., triaz-ines and substituted ureas) have very low toxicity to animals (Table 2.7). The resistance of certain strains of insects to insecticides is due to their possessing a mutant form of the site of action, which is insensitive to the pesticide. Examples include certain strains of housefly with knockdown resistance (mutant form of Na+ channel that is insensitive to DDT and pyrethroids) and strains of several species of insects that are resistant to OPs because they have mutant forms of acetylcholinesterase. These... 

Devonshire, A.L., Byrne, G.D., and Moores, G.D. et al. (1998). Biochemical and molecular characterisation of insecticide sensitive acetylcholinesterase in resistant insects. In Structure and Function of Cholinesterases and Related Proteins, Doctor, B.P, Quinn, D.M., Rotundo, R.L. and Taylor, P. (Eds.) New York Plenum Press, 491 96. 

The carbamate insecticide aldicarb (Figure 2.13) that exerts its effect by inactivating acetylcholinesterase is metabolized by a flavin monooxygenase from rainbow trout to the sulfoxide, which is a more effective inhibitor (Schlenk and Buhler 1991). 

Organophosphate Ester Hydraulic Fluids. Interpretation of the biomarkers of exposure to organophosphate ester hydraulic fluids is complicated by the diversity of composition among the hydraulic fluids in this class. Erythrocyte acetylcholinesterase activity is a good biomarker of exposure to certain organophosphates (e.g., insecticides), but results are inconsistent with organophosphate components of... 

Mutero, A., Pralavorio, M., Bride, J.M. and Fournier, D. (1994) Resistance-associated point mutations in insecticide-insensitive acetylcholinesterase. Proceedings of the National Academy of Sciences USA 91,5922—5926. 

V.B. Kandimalla and H.X. Ju, Binding of acetylcholinesterase to multiwall carbon nanotube-cross-linked chitosan composite for flow-injection amperometric detection of an organophosphorous insecticide. Chem. Eur. J. 12, 1074—1080 (2006). 

S. Andreescu, L. Barthelmebs, and J.L. Marty, Immobilization of acetylcholinesterase on screen-printed electrodes comparative study between three immobilization methods and applications to the detection of organophosphorus insecticides. Anal. Chim. Acta 464, 171—180 (2002). 

Cambon, C., C. Declume, and R. Derache. 1979. Effect of the insecticidal carbamate derivatives (Carbofuran, Pirimicarb and Aldicarb) on the activity of acetylcholinesterase in tissues from pregnant rats and fetuses. Toxicol. Appl. Pharmacol. 49 203-208. 

Misawa, M., J. Doull, P.A. Kitos, and E.M. Uyeki. 1981. Teratogenic effects of cholinergic insecticides in chick embryos. I. Diazinon treatment on acetylcholinesterase and choline acetyltransferase activities. Toxicol. Appl. Pharmacol. 57 20-29. 

Most insecticides, especially the organophosphate group, cause neurotoxicity as their major mode of action. Assessment of the neurotoxicity includes neurochemical endpoints such as cholinesterase (including acetylcholinesterase, which is the major neurotransmitter in vertebrates such as fish, and other enzymes such as butyrylcholinesterase) inhibition and behavioral endpoints such as swimming speed [79]. Studies done in rats show the neurotoxic action of insecticides such as dimethoate, methyl parathion, dichlorvos, ethyl parathion or propoxur after a prolonged exposure [80,81]. 

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