Acetylcholinesterase inhibition organophosphates

Diazinon, an anticholinesterase organophosphate, inhibits acetylcholinesterase in the central and peripheral nervous system. Inhibition of acetylcholinesterase results in accumulation of acetylcholine at muscarinic and nicotinic receptors leading to peripheral and central nervous system effects. These effects... 

Esterase activity is important in both the detoxication of organophosphates and the toxicity caused by them. Thus brain acetylcholinesterase is inhibited by organophosphates such as paraoxon and malaoxon, their oxidized metabolites (see above). This leads to toxic effects. Malathion, a widely used insecticide, is metabolized mostly by carboxylesterase in mammals, and this is a route of detoxication. However, an isomer, isomalathion, formed from malathion when solutions are inappropriately stored, is a potent inhibitor of the carboxylesterase. The consequence is that such contaminated malathion becomes highly toxic to humans because detoxication is inhibited and oxidation becomes important. This led to the poisoning of 2800 workers in Pakistan and the death of 5 (see chap. 5 for metabolism and chap. 7 for more details). 

Organophosphates inhibit acetylcholinesterase, the enzyme responsible for breaking down acetylcholine into acetic acid and choline. After acetylcholine has been... 

How organophosphates are toxic to nerves. Acetylcholine is a neuro-transmitter chemical present in the ends of nerves. Acetylcholinesterase is an enzyme which breaks down acetylcholine so that it is no longer effective at causing muscle contraction. Organophosphates inhibit this enzyme allowing acetylcholine to accumulate. 

Perrier, N.A., Salani, M., Falasca, C., Bon, S., Augusti-Tocco, G., Massoulie, J. (2005). The readthrough variant of acetylcholinesterase remains very minor after heat shock, organophosphate inhibition and stress, in cell culture and in vivo. J. Neurochem. 94 629-38. 

Kuca, K., Patocka, J., Cabal, J. (2003c). Reactivation of organophosphate inhibited acetylcholinesterase activity by a,W-bis-(4-hydroxyuninomethylpyridinium)alkanes in vitro. J. Appl. Biomed. 1 207-11. 

The bispyridinium oxime HI-6, which is a powerful reactivator of imaged organophosphate-inhibited acetylcholinesterase, is eliminated by renal excretion. The allometric equations expressing the relationship between pharmacokinetic parameters describing the elimination of HI-6 and body weight of various mammalian species (mouse, rat, rabbit, Rhesus monkey, Beagle dog, sheep and man) are ... 

Herkenhoff, S. et al. Effect of organophosphoms hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase. Arch. Toxicol, 78, 338, 2004. 

George KM, Schule T, Sandoval LE et al. (2003). Differentiation between acetylcholinesterase and the organophosphate-inhibited form using antibodies and the correlation of antibody recognition with reactivation mechanism and rate. J Biol Chem, 278, 45512-45518. 

Lin AJ and Klayman DL (1986). Stability studies of bis(pyridiniumaldoxime) reactivators of organophosphate inhibited acetylcholinesterase. J Pharm Sci, 75, 797-799. 

Luo C, Ashani Y and Doctor BP (1998a). Acceleration of oxime-induced reactivation of organophosphate -inhibited fetal bovine serum acetylcholinesterase by monoquaternary and bisquaternary ligands. Mol Pharmacol, 53, 718-726. 

Symptoms (a) are due to the excess acetylcholine at muscarinic receptors. Symptoms (b) are due to excess acetylcholine at nicotinic receptors. Symptoms (c) are due to the accumulation of acetylcholine in the central nervous system. Acetylcholine accumulates because the organophosphates inhibit the enzyme acetylcholinesterase which normally removes the neurotransmitter substance. 

Organophosphate pesticides have been reported to both increase and decrease a- and b-wave amplitudes, though this effect may be independent of the organophosphates inhibition of acetylcholinesterase activity (Yoshikawa, et. al. 1990 reviewed in Boyes, et. al.,1994 and Dementi, 1994). Fenthion reduced a- and b-wave amplitudes in both pigmented and albino rats. The albino strain showed a more rapid reduction in amplitude as a function of time, but also produced much greater between animal variability (Imai, et. al., 1983). 

Worek, R, Wille, T., Aurbek, N., et al., 2010. Reactivation of organophosphate-inhibited human, Cynomolgus monkey, swine and guinea pig acetylcholinesterase by MMB-4 a modified kinetic approach. Toxicol. Appl. Pharmacol. 249, 231-237. 

Insecticides and nerve gases act as irreversible inhibitors of acetylcholinesterase, an enzyme needed for nerve conduction. The compound DFP (diisopropyl fluorophosphate), an organophosphate insecticide, forms a covalent bond with the side chain —CH2OH of serine in the active site. When acetylcholinesterase is inhibited, the transmission of nerve impulses is blocked, and paralysis occurs. 

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