Organophosphate compounds acetylcholinesterase inhibition

There is a second type of cholinesterase called butyrylcholinesterase, pseudocholinesterase, or cholinesterase. This enzyme is present in some nonneural cells in the central and peripheral nervous systems as well as in plasma and serum, the liver, and other organs. Its physiologic function is not known, but is hypothesized to be the hydrolysis of esters ingested from plants (Lefkowitz et al. 1996). Plasma cholinesterases are also inhibited by organophosphate compounds through irreversible binding this binding can act as a detoxification mechanism as it affords some protection to acetylcholinesterase in the nervous system (Parkinson 1996 Taylor 1996). 

C. Bronchoconstriction and secretion and muscular weaknesses occur from acetylcholine accumulation after inhibition of acetylcholinesterase. Parathion is an organophosphate insecticide that inhibits acetylcholinesterase, and it is readily available. Poisoning with compound 1080 (fluorocitrate) inhibits mitochondrial respiration and causes seizures and car-... 

Acetylcholine is a neurotransmitter, a key substance involved with transmission of nerve impulses in the brain, skeletal muscles, and other areas where nerve impulses occur. An essential step in the proper function of any nerve impulse is its cessation (see Figure 6.9), which requires hydrolysis of acetylcholine as shown by Reaction 6.10.1. Some xenobiotics, such as organophosphate compounds (see Chapter 18) and carbamates (see Chapter 15) inhibit acetylcholinesterase, with the result that acetylcholine accumulates and nerves are overstimulated. Adverse effects may occur in the central nervous system, in the autonomic nervous system, and at neuromuscular junctions. Convulsions, paralysis, and finally death may result. 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

Worek, F., Kirchner, T, Backer, M.. and Szinicz, L. (1996). Reactivation by various oximes of human erythrocyte acetylcholinesterase inhibited by different organophosphate compounds. Arch. Toxicol. 70, 497-503. 

Fawcett, W.P., Aracava, Y., Adler, M., et al, 2009. Acute toxicity of organophosphate compounds in guinea pig is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition. J. Pharmacol. Exp. 

The inhibition of two cholinesterase activities in blood can also be used to confirm exposure to certain organophosphate ester compounds. Red blood cell acetylcholinesterase is the same cholinesterase found in the gray matter of the central nervous system and motor endplates of sympathetic ganglia. Synonyms for this enzyme include specific cholinesterase, true cholinesterase, and E-type cholinesterase. Plasma cholinesterase is a distinct enzyme found in intestinal mucosa, liver, plasma, and white matter of the central nervous system. Synonyms for this enzyme include nonspecific cholinesterase, pseudocholinesterase, butyrylcholinesterase, and S-type cholinesterase (Evans 1986). Nonspecific cholinesterase is thought to be a very poor indicator of neurotoxic effects. 

Enzymes can be used not only for the determination of substrates but also for the analysis of enzyme inhibitors. In this type of sensors the response of the detectable species will decrease in the presence of the analyte. The inhibitor may affect the vmax or KM values. Competitive inhibitors, which bind to the same active site than the substrate, will increase the KM value, reflected by a change on the slope of the Lineweaver-Burke plot but will not change vmax. Non-competitive inhibitors, i.e. those that bind to another site of the protein, do not affect KM but produce a decrease in vmax. For instance, the acetylcholinesterase enzyme is inhibited by carbamate and organophosphate pesticides and has been widely used for the development of optical fiber sensors for these compounds based on different chemical transduction schemes (hydrolysis of a colored substrate, pH changes). 

Organophosphate or Organophosphorus Compound—A phosphorus containing organic compound, especially a pesticide that acts by inhibiting acetylcholinesterase. 

The major action resulting from human exposure to diazinon is the inhibition of cholinesterase activity (refer to Section 2.4 for discussion). Two pools of cholinesterases are present in human blood acetylcholinesterase in erythrocytes and serum cholinesterase (sometimes referred to as pseudocholinesterase or butyrlcholinesterase) in plasma. Acetylcholinesterase, present in human erythrocytes, is identical to the enzyme present in neural tissue (the target of diazinon action) while serum cholinesterase has no known physiological function. Inhibition of both forms of cholinesterase have been associated with exposure to diazinon in humans and animals (Coye et al. 1987 Edson and Noakes 1960 Soliman et al. 1982). Inhibition of erythrocyte, serum, or whole blood cholinesterase may be used as a marker of exposure to diazinon. However, cholinesterase inhibition is a common action of anticholinesterase compounds such as organophosphates (which include diazinon) and carbamates. In addition, a wide variation in normal cholinesterase values exists in the general population, and there are no studies which report a quantitative... 

The detection of organophosphate and other pesticides based on the inhibition of the enzyme acetylcholinesterase by these compounds has received considerable attention primarily due to high specificity and sensitivity [1,7-16]. Cholinesterases, such as acetylcholinesterase,... 

The term potentiation is then reserved for those cases where both compounds have appreciable intrinsic toxicity, such as in the case of malathion and EPN. Malathion has a low mammalian toxicity due primarily to its rapid hydrolysis by a carboxylesterase. EPN (Figure 9.6) another organophosphate insecticide, causes a dramatic increase in malathion toxicity to mammals at dose levels, which, given alone, cause essentially no inhibition of acetylcholinesterase. The increase in toxicity as a result of coadministration of these two toxicants is the result of the ability of EPN, at low concentrations, to inhibit the carboxylesterase responsible for malathion degradation. 

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