Toxins, organophosphate

Neurotoxin obtained from freshwater blue-green cyanobacteria (Anabaena spp., Aphanizo-menon spp., and Oscillatoria spp.). It is the only known organophosphate toxin produced by cyanobacteria. 

Mazunder, P.K., Gupta, A.K., Kaushik, M.P., Dumar, D., and Dube, S.N. 1997. Cardiovascular effects of an organophosphate toxin isolated from pthychodiscus brevis. BiomedEnviron Sci 10, Ti-ll. 

There is a need to develop methods for P-S bond cleavage since some nerve agents used in chemical warfare are organophosphate toxins that contain P-S as well as P-O bonds. 

Toxin (Enzyme Inhibition) Biosensors Enzyme affectors (inhibitors and activators) that influence the rate of biocatalytic reactions can also be measured. Sensing probes for organophosphate and carbamate pesticides, for the respiratory... 

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). 

Another important example is the nicotinic acetylcholine receptor, which is activated by the agonist nicotine causing muscular fibrillation and paralysis. Indirect effects can also occur. For example, organophosphates and other acetylcholinesterase inhibitors increase the amount of acetylcholine and thereby overstimulate the receptor, leading to effects in a number of sites (see chap. 7). Alternatively, botulinum toxin inhibits the release of acetylcholine and causes muscle paralysis because muscular contraction does not take place (see chap. 7). 

Toxicants may have three effects on pulse rate bradycardia (decreased rate), tachycardia (increased rate), and arrhythmia (irregular pulse). Alcohols may cause either bradycardia or tachycardia. Amphetamines, belladonna alkaloids, cocaine, and tricyclic antidepressants (see imi-primine hydrochloride in Figure 6.12) may cause either tachycardia or arrhythmia. Toxic doses of digitalis may result in bradycardia or arrhythmia. The pulse rate is decreased by toxic exposure to carbamates, organophosphates, local anesthetics, barbiturates, clonidine, muscaric mushroom toxins, and opiates. In addition to the substances mentioned above, those that cause arrhythmia are arsenic, caffeine, belladonna alkaloids, phenothizine, theophylline, and some kinds of solvents. 

As will become clear, this chapter is focused on toxicants for which the receptor is a high-affinity recognition site of the type discussed in the previous paragraphs. It should be noted explicitly that other toxicants have receptors, but fall into more complex situations not appropriate for this chapter. For example, some toxicants inhibit enzymes, or are themselves enzymes. Such interesting compounds include the organophosphate and carbamate insecticides (acetylcholine esterase inhibitors) and diphtheria toxin (an enzyme). 

Efremenko, E.N., and Sergeeva, V.S. (2001) Organophosphate hydrolase - an enzyme eatalyzing degradation of phosphorous-containing toxins and pesticides, Russian Chem. Bui. (Int. Ed.) 50 1826-1832. 

More recently, Mota-Sanchez et al. (2002) found a similar trend using database analysis. Table 10.3 shows that the majority of reported cases of resistance are arthropod resistance to organophosphate (44%) and organochlorine (32%) insecticides. It is understandable, because these two classes of insecticides have been used in pest control for over half a century. As shown in Table 10.4, twelve species of insects have developed resistance to various strains of Bt and Bt toxins in the laboratory and/or the field. 

Incubation of AChE with onchidal resulted in the production of acetate, demonstrating that onchidal was a substrate for AChE, and approximately 3250 mol of onchidal was hydrolyzed/mol of enzyme irreversibly inhibited. Organophosphate and carbamate inhibitors of AChE have partition ratios (mol of toxin hydrolyzed/mol of enzyme irreversibly inhibited) that approach unity. Therefore, the relatively high partition ratio for onchidal suggests that the mechanism of inhibition utilized by onchidal may be distinctly different from other irreversible inhibitors (Walsh, 1984). The rate of hydrolysis of onchidal (Acat) was 325 min this value is relatively slow suggesting that onchidal is not a very good substrate. The ability of AChE to hydrolyze onchidal raised the question of whether inhibition of enzyme activity resulted from onchidal itself or from a product of the enzymatic hydrolysis of onchidal. Enzyme kinetics revealed that onchidal was unable to completely inhibit higher concentrations of AChE. From the experiments performed by Abramson et al. (1989), onchidal was in molar excess and was completely hydrolyzed. Thus,... 

CWAs are represented by any one of a number of chemicals exhibiting a very high toxicity by various mechanisms. The present Handbook exhibits CWAs with structures as simple as carbon monoxide (CO) and as complex as botulinum toxin or ricin proteins. While this chapter could address the development of PBPK models of CWAs in general, the focus will primarily be on the organophosphate (OP)-based nerve agents typically represented by sarin (GB - isopropyl methylfluoro-phosphonate). 

Simonian, A.L., Flounders, A.W., Wild, J.R. (2004). FET-based biosensors for the direct detection of organophosphate nerve toxins. Electroanalysis 16 1896-1906. 

Pyrethroids are ion channel toxins that prolong neuronal excitation. I61 Despite their lipophilic character, pyrethroids are slowly absorbed through the skin and have limited toxicities. When applied with organophosphates,... 

Several potential etiologies were investigated, including infectious agents, pet-borne vectors, contaminated food, organophosphate pesticide exposure, and vinyl chloride contamination from food containers, before a link was made between the new disease and the consumption of adulterated cooking oil. Chemical analysis of the case-associated oil identified brassicasterol, a marker for rapeseed oil, trace amounts of aniline, oleyl anilide, and other fatty acid anilides and contaminants (Aldridge, 1992 Posada de la Paz et al., 1996 Ruiz-Mendez et al., 2001). The toxin or toxins appear to be stable in oil, since consumption of toxic oil one year after the main epidemic led to development of the disease. 

We will begin with phosphotriesterase, which is an unusual (if not unique) enzyme in that it has no naturally occurring substrates. The enzyme was originally isolated from soil bacteria that were able to hydrolyze and detoxify a wide variety of organophosphate insecticides and nerve toxins. A typical reaction is the hydrolysis of the insecticide paraoxon, shown in Equation (2) ... 

Most of the published studies of AN-a(s) in cyanobacteria have involved live animal bioassays a study using mice showed that this toxin has an LD50 of approximately 50 fig/kg (i.p.) (Mahmood and Carmichael, 1986). The same authors also observed the acetyl chohnesterase inhibition that is characteristic of AN-a(s). The inhibitory effect of this toxin remains the most effective means of detection and has been exploited in an assay using electric eel acetylcholinesterase (Mahmood et al., 1988) and in a number of subsequent bioassays. Although the inhibitory effect of AN-a(s) is similar to synthetic organophosphate insecticides, it was shown that AN-a(s) as an active site-directed... 

Pharmacologic effects of toxins, eg, organophosphate or carbamate insecticides or beta-adrenergic blockers. 

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