Butyrylcholinesterase

Galanthamine (23) is an alkaloid extracted from the common snowdrop Galanthus nivalis. This compound is a long-acting, competitive AChE inhibitor which appears to be somewhat more specific for acetylcholinesterase than plasma butyrylcholinesterase (132). It is well tolerated during long-term treatment (133) and is being evaluated clinically for AD (134). 

Metrifonate [52-68-6] (24) is itself not an AChE inhibitor, but is none2ymaticaIly converted into an active irreversible inhibitor of the en2yme. The compound is relatively specific for AChE over butyrylcholinesterase (135) and the irreversible nature of its inhibition gives rise to an extended duration of action. Some clinical experience has been gained through its use to treat schistosomiasis (136,137) and it is undergoing clinical evaluation for AD. 

Acetylcholinesterase (EC 3.1.1.7) (AChE) Acetylcholine acetylhydrolase True ChE ChE I ChE Acet-ylthiocholinesterase Acetylcholine hydrolase Acetyl (3-methylcholinesterase Erythrocyte ChE Butyrylcholinesterase (EC 3.1.1.8) (BChE or BuChE) ChE Pseudocholinesterase Plasma ChE Acylcholine acylhydrolase Non-specific ChE ChEII Benzoylcholinesterase Propionylcholinesterase... 

Butyrophenones Butyrylcholinesterase C2 Domain C Kinase C-reactive Protein Ca2+-ATPase Ca2+-binding Proteins Ca2+ Channel Ca2+ Channel Antagonists Ca2+ Channel Blockers... 

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). 

Acetylcholine, acetylcholinesterase, and butyrylcholinesterase are involved in the development of the nervous system (Brimijoin and Koeninsberger 1999 Layer 1990 Layer and Willbold 1994) some of this development is not complete until adulthood. Therefore, toxic chemicals acting on these substances could cause deleterious developmental effects in addition to the typical physiological effects already discussed. 

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. 

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... 

Bd Wt = body weight BuChE = butyrylcholinesterase Cardio = cardiovascular CEL = cancer effect effect level contin = continuous d = day(s) Derm = dermal Endocr = endocrine F = female Gastro = gastrointestinal Gd = gestation day(s) Gn pig = guinea pig Hemato = hematological hr= hour(s) LC50 = lethal concentration, 50% kill LOAEL = lowest-observed-adverse-effect level M = male min = minute(s) mo = month(s) Musc/skel = musculoskeletal NOAEL = no-observed-adverse-ettect level NS = not specified Resp = respiratory wk = week(s)... 

Kjellstrand P, Hohnquist B, Aim P, et al. 1983a. Trichloroethylene Further studies of the effects on body and organ weights and plasma butyrylcholinesterase activity in mice. Acta Pharmacol Toxicol 53 375-384. 

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... 

The dual inhibition of acetylcholinesterase and butyrylcholinesterase may lead to broader efficacy. As acetylcholinesterase activity decreases with disease progression, the acetylcholinesterase-selective agents may lose their effect, while the dual inhibitors may still be effective due to the added inhibition of butyrylcholinesterase. However, this has not been demonstrated clinically. 

Consistent decreases in plasma cholinesterase may not have been observed in rats and dogs because they were treated with lower doses of diisopropyl methylphosphonate. In general, depression of plasma cholinesterase, also known as pseudocholinesterase or butyrylcholinesterase, is considered a marker of exposure rather than an adverse effect. Depression of cholinesterase activity in red blood cells (acetylcholinesterase) is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity. It is considered an adverse effect. Acetylcholinesterase is found mainly in nervous tissue and erythrocytes. Diisopropyl methylphosphonate was not found to inhibit RBC... 

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). 

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. 

Richardson RJ, Moore TB, Kayyali US, et al. 1993. Chlorpyrifos Assessment of potential for delayed neurotoxicity by repeated dosing in adult hens with monitoring of brain acetylcholinesterase, brain and lymphocyte neurotoxic esterase, and plasma butyrylcholinesterase activities. Fundam Appl Toxicol 21 89-96. 

Jbilo, O., Bartels, C.F., Chatonnet, A., Toutant,J.P. and Lockridge, O. (1994) Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger RNA. Toxicon 32, 1445-1457. 

Stone et al. use this method to simultaneously synthesize the silica and entrap the butyrylcholinesterase which retains all its activity after the process of encapsulation, a high enzyme loading (90 %) is reached and the stability is increased [168]. The method has been further developed to simultaneously entrap catalase and horseradish peroxidase with inorganic magnetic nanopartides [169] which will fadlitate the separation [170,171]. 

Most of the pesticide biosensors are designed based on the inhibitory property of enzymes. AChE and butyrylcholinesterase (BChE) are widely used in the development of pesticide biosensors [17, 18], Inhibition leads to a decrease in activity, which... 

Giacobini, E. (ed.) Butyrylcholinesterase its Function and Inhibitors. London Martin Dunitz, 2003. 

Donepezil (Aricept) is a piperidine derivative with specificity for inhibition of acetylcholinesterase rather than butyrylcholinesterase. 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

Fidder, A., Hulst, A.G., De Ruiter, R., Van Der Schans, M.J., Benschop, H.P., and Langenberg, J.P., (2002). Retrospective detection of exposure to organophosphorus anticholinesterases mass spectrometric analysis of phosphylated human butyrylcholinesterase. Chem. Res. Toxicol., 15, 582-590. 

Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen EG, Masson P, Lockridge O (2005) Butyrylcholinesterase, paraoxonase, and albumin esterase, but no carboxylesterase, are present in human plasma. Biochem Pharmacol 70 1673-1684... 

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]. 

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

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