BuChE inhibition

Blood Fluoride reactivation method Phospho-rylated BuChE (+ other proteins) GC-MS GC-HR-MS With large volume injection Phosphonofluo- ridates i.s. deuterated OP or plasma exposed to deuterated OP Easily accessible internal standards and reference compounds LOD 10 pg/ml (0.05-0.1% BuChE inhibition) Not applicable to all OP s... 

Blood Analysis of phospho-rvlated peptides Phosphyla-ted BuChE LC-MS-MS (after enzymatic digestion of modified cholinesterase. Phosphylated nonapeptides i.s. plasma exposed to CD3-OP Covers all OP s LOD 1-5% BuChE inhibition Expensive instrumentation and reference compounds... 

ChEI Dose mg/kg (pmol/kg) AChE Inhibition (%) (n = 6) BuChE Inhibition (%) Cortex Hippocampus Striatum Semm (n —3) ... 

FIG. 13, (A) Plasma time course of diazinon (DZN), (B) plasma BuChE inhibition, and (C) pla.sma AChE inhibition in rats following oral administration of 50 (gray) or 100 (black) mg DZN/kg of body weight, respectively. The linc.s represent the model simulation of the experimental data. Adapted with permission from Poet et al. (2004). 

FIG. 20. Simulation of peak pla,sma BuChE inhibition dosc-responsc in humans following an acute exposure lo a broad range of chlorpyrifos doses. Adapted with permission from Timchalk etal. (2002a). 

For the purpose of establishing ADls, the inhibition of plasma and brain butyrylcholincstcrase (BuChE) is not a toxicologiciUly significant effect because there is no evidence that BuChE inhibition has any adverse effect. 

ZT-1, a semisynthetic prodrug of hupA, is transformed nonenzymaticafly into hupA. It has been administered by i.v., oral, immediate-release and by sustained-release formulations in the form of implants [76]. In vitro studies show that ZT-1 inhibits AChE similar to hupA, but a weaker BuChE inhibition was observed. Pharmacokinetic studies suggest that ZT-1 has similar properties to hupA regarding oral bioavailability, the ability to cross the BBB, and longevity of action [8]. 

In this scheme, EOH is the enzyme, IX is the inhibitor (either a carbamate or an organophosphate). EOH(IX) is analogous to the Michaelis Menton comploc seen with the substrate reaction. EOI is the acyl-enzyme intermediate for carbamates or a phosphoro-enzyme intermediate for the organophosphates. The equilibrium constant for this reaction (K ) is defined as k /k and the phosphorylation or carbamylation constant is defined as k2- In this study 42)y ANTX-A(S) was found to be more specific for AChE than BUChE. The double reciprocal and Dixon plot of the inhibition of electric eel AChE indicated that the toxin is a non-competitive inhibitor decreases, k remains unchanged) (Figure 2). 

Fent, K. and T.D. Bucheli. 1994. Inhibition of hepatic microsomal monooxygenase system by organotins in vitro in freshwater fish. Aquat. Toxicol. 28 107-126. 

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. 

To avoid the undesirable effects of excess cholinergic stimulation, ACh is rapidly hydrolyzed after its release at the synapse by an enzyme named acetylcholinesterase AChE. A similar enzyme, butylcholinesterase BuChE also occurs. If the cholinesterase is inhibited, the ACh is not hydrolyzed so rapidly, and levels of ACh rise. 

As well as inhibiting AChE, physostigmine also inhibits butyl-cholinesterase (BuChE) another enzyme found in the CNS. BuChE has recently been implicated in the aetiology and progression of AD. Inhibition of BuChE may therefore prove to be beneficial in treating AD, particularly because BuChE has been shown to produce fl-amyloid proteins and to enable them to diffuse into the plaques observed in neurons of AD... 

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

Rutaecarpine (46) is the major alkaloid found in Evodia rutaecarpa (Juss.) Benth., and activities relevant to AD have been identified with the extract and with rutaecarpine. Dehydroevodiamine (47), another alkaloid from the same species, inhibited AChE in vitro, and reversed scopolamine-induced memory impairment in rats and increased cerebral blood flow in vivo in cats, a property which would supplement its usefulness in AD. The structures of (46) and (47) and tacrine (28) have been used as templates for the development of a series of synthetic compounds which have been evaluated for their antiChE activity. These were found to be inhibitory against both AChE and BuChE with A -(2-phenylethyl)-A -[(12Z)-7,8,9,10-tetrahydroazepino [2,l- ]quinazolin-12(6//)-ylidene] amine (48) showing higher affinity for BuChE. 

A number of steroidal alkaloids isolated from Fritillaria species have been evaluated for their ability to inhibit both AChE and BuChE in vitro, with yibeinoside A (58) giving the greatest activity (IC50 6.5 xM and 7.3 xM against AChE and BuChE respectively. ... 

Enzymes inhibited Acetylcholinesterase (AChE) AChE, butyryl-cholinesterase (BuChE) AChE... 

FIGURE 12-25. Icon for the cholinesterase inhibitor tacrine. This was the first cholinesterase inhibitor, but since it is a hepatoxotin, it has been relegated to second-line use. Also, it must be given four times daily, is difficult to dose, and has several drug interactions. It is short-acting, reversible, and nonselective, inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). 

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