Cholinesterase Acetylcholinesterase

Although this study (Hart 1980) did not identify an effect level, the NOAEL is below the LOEL found in all studies examining the toxicity of diisopropyl methylphosphonate. The LOEL for diisopropyl methylphosphonate is 262 mg/kg/day for male mink and 330 mg/kg/day for female mink (Bucci et al. 1997), doses at which statistically significant decreases in plasma cholinesterase (butyrylcholinesterase) but not RBC cholinesterase (acetylcholinesterase) activity were observed (Bucci et al. 1997). In general, a decrease in plasma cholinesterase activity is considered to be a marker of exposure rather than a marker of adverse effect, while a decrease in RBC acetylcholinesterase activity is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity and is thus considered an adverse effect. Diisopropyl methylphosphonate was not found to inhibit red blood cell cholinesterase at doses at which plasma cholinesterase was significantly inhibited. No effects were observed in males at 45 mg/kg/day (Bucci et al. 1997) or at 63 mg/kg/day (Bucci et al. 1994), and no effects were observed in females at 82 mg/kg/day (Bucci et al. 1994), or at 57 mg/kg/day (Bucci et al. 1997). 

Esterases that contribute to human drug metabolism fall into three major classes the cholinesterases (acetylcholinesterase, pseudocholinesterase, butyrylcholinesterase, etc.),... 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

There are two major types of cholinesterases acetylcholinesterase (AChE) and pseudocholinesterase (pseudo-ChE). AChE (also known as true, specific, or erythrocyte cholinesterase) is found at a number of sites in the body, the most important being the cholinergic neuroeffector junction. Here it is localized to the prejunctional and postjunctional membranes, where it rapidly terminates the action of synaptically released ACh. It is essential to recognize that the action of ACh is ter-... 

The body contains two main classes of cholinesterase acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase (EC 3.1.1.8).27 The former, sometimes referred to as true cholinesterase, Is mainly a tissue enzyme and Is found mainly In such tissues as the synapses of the cholinergic system It Is also found In other tissues, such as erythrocytes, where Its function Is uncertain. The latter, referred to as pseudocholinesterase, Is a soluble enzyme that is synthesized In the liver and circulates in the plasma-... 

PAM is given to regenerate inhibited cholinesterase (acetylcholinesterase) enzyme at all affected sites (Schenker et al. 1992 Shankar 1967, 1978). The available information sufficiently satisfies the need for methods of reducing toxic effects. Therefore, further studies in this regard are not required. 

Acyl Cholinesterases. Acetylcholinesterase (AChE EC 3.1.1.7 CAS 9000-81-1) is the serine esterase which catalyzes the hydrolysis of acetylcholine and possesses an esteratic site, and which is responsible for unspecific hydrolyses of several substrates. Also, butyrylcholinesterase (EC 3.1.1.8 CAS 9001-08-5) has been sometimes used for asymmetric hydrolysis of esters. Acetylcholinesterase has been used for... 

Pseudocholinesterase deficiency. The neuromuscular blocking action of suxamethonium is terminated by plasma pseudocholinesterase. True cholinesterase (acetylcholinesterase) hydrolyses acetylcholine released by nerve endings, whereas various tissues and plasma contain other nonspecific, hence pseudo, esterases. Affected individuals form so little plasma pseudocholinesterase that metabolism of suxamethonium is seriously reduced. The deficiency characteristically comes to light when a patient fails to breathe spontaneously after a surgical operation, and assisted ventilation may have to be undertaken for hours. Relatives of an affected individual—for this as for other inherited abnormalities carrying avoidable risk—should be sought out, checked to assess their own risk, and told of the result. The prevalence of pseudocholinesterase deficiency in the UK population is about 1 in 2500. 

Cholinergic medication (cholinesterase inhibitors, anticholinesterase) has either a direct- or indirect-acting effect on receptor sites. Direct and indirect effects inhibit the action of the enzyme cholinesterase (acetylcholinesterase). By inhibiting cholinesterase, more acetylcholine is available to stimulate the receptor and remains in contact with the receptor longer. 

One of the pillars upon which rests the prevailing theory of the chemical mediation of nerve impulses is the uniqueness, in conducting tissue, of the enzyme that hydrolyzes acetylcholine. The characteristics of acetylcholinesterase that distinguish it from the other cholinesterases are as follows (1) A small Km when acetylcholine is the substrate. (2) Inhibition of the hydrolysis of acetylcholine by the substrate so that when the velocity is plotted against substrate concentration a bell-shaped curve results. (3) A rate of hydrolysis that is greatest with acetylcholine, less with propionylcholine, and the least with butyrylcholine. None of these properties is shared by the other cholinesterases. Acetylcholinesterase occurs, however, not only in conducting tissue but also in erythrocytes and cobra venom. The distribution of cholinesterases has been reviewed by Augustinsson. ... 

True or red cell cholinesterase (acetylcholinesterase). This is found predominantly in erythrocytes and nervous tissue. 

ACETYLCHOLINESTERASE INHIBITING PESTICIDES Cholinesterase activity in red Discretionary 70% of individuals Ns... 

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). 

Following exposure of humans to organophosphates, but not specifically methyl parathion, restoration of plasma cholinesterase occurs more rapidly than does restoration of erythrocyte cholinesterase (Grob et al. 1950 Midtling et al. 1985). These findings are supported by studies of methyl parathion in animals. Erythrocyte cholinesterase levels are representative of acetylcholinesterase levels in the nervous system, and, therefore, may be a more accurate biomarker of the neurological effects of chronic low level exposure of humans to methyl parathion (Midtling et al. 1985 NIOSH 1976). 

Individuals with hereditary low plasma cholinesterase levels (Kalow 1956 Lehman and Ryan 1956) and those with paroxysmal nocturnal hemoglobinuria, which is related to abnormally low levels of erythrocyte acetylcholinesterase (Auditore and Hartmann 1959), would have increased susceptibility to the effects of anticholinesterase agents such as methyl parathion. Repeated measurements of plasma cholinesterase activity (in the absence of organophosphate exposure) can be used to identify individuals with genetically determined low plasma cholinesterase. 

In a study of 135 workers in the ehemical industry who handle methyl parathion, the methyl parathion concentration in plasma, the 4-nitrophenol concentration in urine, and the cholinesterase and acetylcholinesterase activities were determined to assess the pesticide burden in such workers (Leng and Lewalter 1999). The mean concentration of methyl parathion in the plasma of the workers was 233 pg/L no clinical symptoms were reported by the workers. In an additional group of 19 workers handling methyl parathion, who were also exposed to the pyrethroid cyfluthrin, the mean concentrations of methyl parathion in plasma were 269 and 241 pg/L (for groups without and with clinical S5miptoms, respectively), and 7 of the workers exhibited skin paraesthesia, while none of the 427 workers exposed only to the pyrethroid experienced the symptom (Leng and Lewalter 1999). 

Other additional studies or pertinent information that lend sunnort to this MRL Methyl parathion affects the nervous system by inhibiting acetylcholinesterase activity. Cholinesterase inhibition and neurological effects have been observed in humans and animals, for all exposure routes and durations (for example. Dean et al. 1984 Desi et al. 1998 EPA 1978e Gupta et al. 1985 Nemec et al. 1968 Suba 1984). 

Cholinesterases are another group of B-esterases. The two main types are acetylcholinesterase (EC 3.1.1.7) and unspecific or butyrylcholinesterase (EC 3.1.1.8). Acetylcholinesterase (AChE) is found in the postsynaptic membrane of cholinergic... 

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. 

Released ACh is broken down by membrane-bound acetylcholinesterase, often called the true or specific cholinesterase to distinguish it from butyrylcholinesterase, a pseudo-or non-specific plasma cholinesterase. It is an extremely efficient enzyme with one molecule capable of dealing with something like 10000 molecules of ACh each second, which means a short life and rapid turnover (100 ps) for each molecule of ACh. It seems that about 50% of the choline freed by the hydrolysis of ACh is taken back into the nerve. There is a wide range of anticholinesterases which can be used to prolong and potentiate the action of ACh. Some of these, such as physostigmine, which can cross the blood-brain barrier to produce central effects and neostigmine, which does not readily... 

Donepezil is a piperidine cholinesterase inhibitor, which reversibly and non-competitively inhibits centrally active acetylcholinesterase 34 This specificity is claimed to result in fewer peripheral side effects as compared to the other ChE inhibitors. 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

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