Organophosphates inhibition

Liu PS, Kao LS, Lin MK. 1994. Organophosphates inhibit catecholamine secretion and calcium influx in bovine adrenal chromaffin cell. Toxicology 90 81-91. 

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... 

It should also be appreciated that even though a reactive chemical reacts covalently with a protein such as an enzyme, this may not lead to toxicity. This could be due to the protein not having a critical function or there being significant reserves of activity for an enzyme so that even if it is inhibited, sufficient activity remains (e.g., organophosphate inhibition of cholinesterases, see chap. 7). 

PC12 Rat pheochromocytoma (adrenal medullary tumor) Adrenergic neuron Tricresyl phosphate (organophosphate) Inhibition of neurofilament assembly and axonal growth... 

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

In principle, organophosphate-inhibited BuChE in human plasma is a persistent (half-life 5-16 days) and relatively abundant (plasma concentration approximately 80 nM) source for biomonitoring of exposure to organophosphate anticholinesterases. Polhuijs et al. (44) developed a procedure for the analysis of phosphylated binding sites, for example,... 

Figure 9. Fluoride reactivation of organophosphate-inhibited butyrylcholinesterase. (Reprinted from Toxicology and Applied Pharmacology, Vol. 184, D. Noort, H.P. Benschop and R.M. Black, Biomonitoring of Exposure to Chemical Warfare Agents A Review, pages 116-126 (2002), with permission from Elsevier Science.)...

Esterases that metabolize organophosphates can be divided into three groups A-esterases, which are not inhibited by organophosphates but hydrolyze them B-esterases, which are susceptible to organophosphate inhibition and C-esterases, which are uninhibited by organophosphates and do not degrade them. 

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. 

Li, H., Schopfer, L.W., Nachon, F., Froment, M-T., Masson, P., Lockridge, O. (2007). Aging pathways for organophosphate-inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry. Toxicol. Sci. 100 136 5. 

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. 

Luo, C. et al. Strategy for reactivation of organophosphate-inhibited human butyrylchobnesterase, in Cholinesterases in the Second Millenium Biomolecular and Pathological Aspects, Inestrosa, N.C. and Campos, E.O., Eds., Diseno e Impresiones J J Ltda, Chile, 251, 2004. 

Masson, P. et al. Importance of aspartate-70 in organophosphate inhibition oxime re-activation and aging of human butyrylchohnesetrase, Biochem. J., 325, 53, 1997. 

Saxena, A. et al. Edrophonium as a reactivator of organophosphate-inhibited human butyrylcholinesterase, presented at the Second Singapore International Symposium on Protection Against Toxic (SISPAT) Substances, Singapore, 4-7 December 2000. 

E2. Ecobichon, D. J., and Gomeau, A. M., Pseudocholinesterase of mammalian plasma. Physiochemical properties and organophosphate inhibition in eleven species. Toxicol. Appl. Pharmacol. 24, 92-100 (1973). 

Maksimovich, T., Bregovec, I., Deljac, V., andBinenfeld, Z., Reactivators of organophosphate-inhibited cholinesterase 4-cycloalkylcarbonyl substituted bis-pyridinium monoximes, Arch. Toxicol., 55,1990202,1984. 

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. 

Table 2. Reactivation constants of organophosphate-inhibited human erythrocyte AChE...

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. 

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