Acetyl cholinesterase inhibitors

Many pesticides are neurotoxicants poisoning the nervous system. A number of pesticides are acetyl cholinesterase inhibitors (Serat and Mengle 1973). Generally, pesticides determination has been performed by GC since the 1960 s (Morrison and Durham 1971 Fournier et al. 1978). There are no reference materials for pesticides in urine or serum, although as with PAHs there are a number biological matrices certified for the content of various pesticides available for environmental food and agriculture analysis and which may have some application in clinical chemistry. 

The UK Pesticide Safety Directorate (PSD) has decided to use the TEF approach for assessment of combined risk from exposure to mixtures of acetyl cholinesterase inhibitors (organophosphate (OP) compounds and carbamates) (PSD 1999). Despite clear differences in the action of carbamates and OP compounds, the index compounds selected for all acetyl cholinesterase inhibitors were either aldicarb (carbamate) or chlorpyrifos (OP). The POD for determining relative potency was predetermined as the dose level that produced 20% inhibition of red blood cell cholinesterase in a 90-day dietary study in rats. 

Suvanine (358), an acetyl cholinesterase inhibitor was first isolated from species of Ircinia [316] and then later from a Coscinoderma species from Fiji and Palau when the structure was revised [317]. 

Improvements in medication by use of acetyl cholinesterase inhibitors and general therapy significantly reduce symptoms at the onset of the disease [3, 4] but do not address the severe mortality in the final stages. A causal therapy is, therefore, still very much in demand, because no existing therapy effectively stops or even cures the disease. Identification of gene mutations linked to Alzheimer s disease-afflicted families in London and Sweden and additional polymorphisms that either cause or promote Alzheimer s disease have provided some insight into the biological pathways and the involvement of the amyloid precursor protein (APP) [5-8],... 

By disrupting the biological function of the enzyme acetylcholinesterase, insecticides such as aldicarb, parathion and methamidophos (WHO la) prevent neurotransmitter molecules from being broken down, causing them to accumulate In the spaces between nerve cells. In this way acetyl-cholinesterase inhibitors effectively jam the transmission of nervous signals between nerve cells. 

Racchi, M., MazzucchelU, M., Porrello, E., Lanni, C., Govoni, S. Acetyl cholinesterase inhibitors novel activities of old molecules. Pharma. Res. 2004, 50, 441 51. 

These compounds act as inhibitors in acetyl-cholinesterase metabolism5-113115 and are absorbed via inhalation, mouth, skin or muscous membranes of the eye. For Sarin, the LDI00 value for humans is expected to be 0.04-0.06 mg 1 kg-57... 

For determination of how these inhibitors interact with housefly acetyl cholinesterase the method of Aldridge and Davidson(3) was employed. The log % residual activity is plotted against (molar concentration)(incubation time). When straight line results, it is interpreted that the enzyme-inhibitor interaction is governed by pseudo first order kinetics and is a bimolecular reaction. For the... 

Rlvastigmlne Rivastigmine is a cholinesterase inhibitor which increases acetyl-... 

Cadelli, D. and Schwab, M. E., Regeneration of lesioned septo-hippocampal acetyl-cholinesterase-positive axons is improved by antibodies against the myelin-associated neurite growth inhibitors NI-35/250, Eur. J. Neurosci., 3, 825, 1991. 

The reactions show some typical oxidations of insecticides catalyzed by CYP enzymes. Carbofuran is hydroxylated to another active compound carbaryl is demethylated or hydroxylated and aldrin is epoxidated to diel-drin, which also has insecticidal properties. Phosphorothionates must be oxidized to the phosphates by CYP enzymes in order to become inhibitors of acetyl cholinesterase. Parathion-methyl is transformed to the oxon analogue, paraoxon-methyl, which is the toxic compound. It also can be demethylated to the inactive desmethyl-parathion-methyl. 

White B. J., Legako J. A., and Harmon, H. J., Spectrophotometric detection of cholinesterase inhibitors with an integrated acetyl-Zbutyrylcholinesterase surface. Sens. Actuators B, 89, 107-111, 2003. 

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