Acetylcholinesterase inhibition

Acetylcholine is a neurotransmitter that functions in conveying nerve impulses across synaptic clefts within the central and autonomic nervous systems and at junctures of nerves and muscles. Following transmission of an impulse across the synapse by the release of acetylcholine, acetylcholinesterase is released into the synaptic cleft. This enzyme hydrolyzes acetylcholine to choline and acetate and transmission of the nerve impulse is terminated. The inhibition of acetylcholineasterase results in prolonged, uncoordinated nerve or muscle stimulation. Organophosphorus and carbamate pesticides (Chapter 5) along with some nerve gases (i.e., sarin) elicit toxicity via this mechanism. 

Xenobiotics compete with acetylcholine for binding to the substrate-binding site of the enzyme resulting in reversible or irreversible inhibition of the enzyme. 

The acetyl group is removed from the enzyme by hydrolysis and the enzyme is regenerated 

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Of the known cyanobacterial toxins only anatoxin-fl(s) is detected and is, therefore, able to be screened for by acetylcholinesterase inhibition. 

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

Functional neurological changes due to acute organophosphate exposure generally correlate with acetylcholinesterase inhibition in erythrocytes (Wills 1972). 

Maxwell DM, Brecht KM. 1992. Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analougues of organophosphorus compounds. Chem Res Toxicol 5 66-71. 

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. 

In cases where the mode of action is the strong or irreversible inhibition of an enzyme system, the assay may measure the extent of inhibition of this enzyme. This may be accomplished by first measuring the activity of the inhibited enzyme and then making comparison with the uninhibited enzyme. This practice is followed when studying acetylcholinesterase inhibition by organophosphates (OP). Acetylcholinesterase activity is measured in a sample of tissue of brain from an animal that has been exposed to an OP. Activity is measured in the same way in tissue samples from untreated controls of the same species, sex, age, etc. Comparison is then made between the two activity measurements, and the percentage inhibition is estimated. 

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). 

Sandahl, J.F, Baldwin, D.H., and Jenkins, J.J. et al. (2005). Comparative thresholds for acetylcholinesterase inhibition and behavioural impairment in Coho Salmon exposed to chlorpyriphos. Environmental Toxicology and Chemistry 24, 136-145. 

Ecothiophate iodide and denecarium bromide inhibit acetylcholinesterase. Inhibition of this enzyme increases the availability of acetylcholine at the nerve junction, thus increasing the stimulation of the muscarinic (M3) receptors of the ciliary... 

Symptoms and Sites of Acetylcholinesterase Inhibition by Organophosphate Esters... 

Two types of OPIDN have been described in animals (Abou-Donia and Lapadula 1990). Type I is produced by compounds with a pentavalent phosphorus (like TOCP), and Type II is produced by compounds with a trivalent phosphorus. Characteristics used to differentiate between the types of OPIDN include species selectivity, age sensitivity, length of latent period, and morphology of neuropathologic lesions. Thus, at doses that did not produce death due to acetylcholinesterase inhibition, TOCP (a Type I compound) produced lesions in the spinal cord of rats without producing ataxia. In contrast, triphenyl phosphite (a Type II compound) produced delayed (1 week) ataxia in the rat and a distribution of spinal cord lesions distinct from those produced by TOCP (Abou-Donia and Lapadula 1990). 

Organophosphate Ester Hydraulic Fluid. The most widely examined target of organophosphate ester hydraulic fluids is the nervous system. Two types of neurological effects have been observed following exposure to certain organophosphate ester hydraulic fluids cholinergic symptoms associated with acetylcholinesterase inhibition and delayed neuropathy (OPIDN). 

Consequences of acetylcholinesterase inhibition differ with effector site 197... 

Consequences of acetylcholinesterase inhibition differ with effector site. At postganglionic parasympathetic effector sites, AChE inhibition enhances or potentiates the action of administered ACh or ACh released by nerve activity. In part, this is a consequence of diffusion of... 

Bourne, Y., Taylor, P. and Marchot, P. Acetylcholinesterase inhibition by fasciculin. Crystal structure of the complex. Cell 83 503-512,1995. 

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