Acetylcholinesterase inhibition, mechanism

Camptothecin derivatives and acetylcholinesterase inhibition Mechanism and treatment of delayed onset diarrhoea induced by CPT-11... 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

Mechanistic biomarker A biomarker that provides a measure of a toxic effect (some biomarkers only measure exposure). In the simplest case, this involves the direct measurement of the operation of a mechanism of toxicity (e.g., of acetylcholinesterase inhibition). 

Melchers, B.P.C., Van der Laaken, A.L., Van Helden, H.P.M. (1991). On the mechanism whereby HI-6 improves neuromuscular function after oxime-resistant acetylcholinesterase inhibition and subsequent impairment of neuromuscular transmission. Eur. J. Pharmacol. 200 331-7. 

The specific mechanism of toxicity of kerosene has not been completely determined. The primary risk from ingestion of kerosene is aspiration during emesis, which may cause pneumonitis. The biochemical mechanism of lung response to large concentrations of aerosolized kerosene (resulting in bronchocon-striction and asthma-like symptoms) may involve the parasympathetic nervous system via a direct effect on the vagus nerve or by inhibition of acetylcholinesterase. The mechanism(s) of central nervous system (CNS) depression from kerosene exposure has not been elucidated, but undoubtedly includes disruption of the membranes of nerve cells. 

There are three mechanisms by which detectors may work (i) acetylcholinesterase inhibition (ii) a chemical reaction specific for nerve agents and (iii) some sort of physical measurement. In the first type, butyrylthiocholine (this is much like ACh, with the major difference being that one of the oxygens is replaced by a sulphur) is continually presented to AChE as long as there is no nerve agent present, this is converted into thiocholine, just like the conversion of ACh into choline (see Fig. 3). The thiocholine is then measured by a chemical reaction which produces a colour. If a nerve agent is present, then the AChE is inhibited, the production of thiocholine is decreased, and this decrease is measured by the degree of the loss of the colour. 

FIGURE 3.4 Mechanism of action of acetylcholinesterase inhibition (A) Structure of AChE (B) normal functioning of AChE (C) inhibition of AChE by nerve agent sarin. (Adapted from Somani et al. )... 

Figure 2.6 Acetylcholinesterase inhibitors (ACHI) prevent acetylcholine degradation by inhibiting the enzyme acetylcholinesterase. The mechanisms of enzyme inhibition are described in the text (left).

Fig. 3.4 General inhibition mechanism of acetylcholinesterase by organophosphate pesticides (Santos et td. 2007)...

Ginkgo s inhibitory effect on the production of amyloid-beta protein has also been mediated by other mechanisms, such as acetylcholinesterase inhibition, modulation of amyloid protein oligomeric species, and lowering of free cholesterol levels." ... 

Jianmongkol, S., Marable, B.R., Berkman, C.W, et al., 1999. Kinetic evidence for different mechanisms of acetylcholinesterase inhibition by (IR)- and (IS)-stereoisomers of isomalathion. Toxicol. Appl. Pharmacol. 155, 43-53. 

Carbamates - Structure activity relationships have been studied with respect to toxicity and anticholinesterase activity. 9 The mechanism of acetylcholinesterase inhibition by the carbamates is not entirely clear. 

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). 

Diabetic patients have reduced antioxidant defences and suffer from an increased risk of free radical-mediated diseases such as coronary heart disease. EC has a pronounced insulin-like effect on erythrocyte membrane-bound acetylcholinesterase in type II diabetic patients (Rizvi and Zaid, 2001). Tea polyphenols were shown to possess anti-diabetic activity and to be effective both in the prevention and treatment of diabetes (Choi et al, 1998 Yang et al, 1999). The main mechanism by which tea polyphenols appear to lower serum glucose levels is via the inhibition of the activity of the starch digesting enzyme, amylase. Tea inhibits both salivary and intestinal amylase, so that starch is broken down more slowly and the rise in serum glucose is thus reduced. In addition, tea may affect the intestinal absorption of glucose. 

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