Anticholinesterase OPs

Poisoning by anticholinesterase OP nerve agents is often characterized by abnormal muscle activity (such as fasciculations) and myopathy (muscle fiber necrosis). The severity of necrosis appears to be correlated with the frequency and duration of the fasciculations. Gupta et al. (1985, 1986, 1987) and Misuhs et al. (1987) demonstrated that both soman and DFP produced musele toxieity, although soman had its predominant aetion through CNS... 

Organophosphorous anticholinesterases (OPs), usually acid anhydride derivatives of phosphoric acid, are among the most toxic substances identified. Originally, OP were developed for use as insecticides, but their extreme toxicity toward higher vertebrates has led to their adoption as weapons of warfare." The OPs most com-... 

For many decades, it has been thought that the interactions of the anticholinesterase OP and CM compounds with AChE and BuChE are kinctically analogous to those of ACh. In the absence of binding of ACh to the peripheral anionic site of AChE (the validity of this assumption is discu.s.sed later), hydrolysis of ACh by AChE or BuChE can be de,scribed by a Ping Pong Bi Bi kinetic scheme (Fig. 5). In this scheme, ACh represents the first substrate, whereas water represents the second. Additionally, choline is the first product formed, and it is released before the second... 

OPs are phosphorus derivatives, many of which are esterase inhibitors, most notably inhibitors of cholinesterases. Their structures vary (see Table 10.1). The anticholinesterase OPs are esters of phosphoric, phosphonic or phos-phorothioic or related acids. The term OP is often used as a shorthand for... 

OP anticholinesterase, but strictly speaking herbicides such as glyphosate and glufosinate-ammonium are OPs. The general formula of anticholinesterase OPs is shown in Figure 10.1 ... 

All of the anticholinesterase OPs have the same qualitative anticholinesterase action, and this property is responsible for their acute lethal effects. However, quantitative differences in toxicity occur and these are partly due to differences in absorption, distribution, metabolism and excretion. Also, the rates of formation of the OP-acetylcholinesterase complex, of hydrolysis of this complex, and of the aging reaction (see below) must be considered. 

Chemical warfare agents, such as soman and sarin, sometimes termed nerve gases, are powerful anticholinesterases, which bear some resemblance in structure and properties, to the OP insecticides. A major difference from most insecticides is their high volatility. These agents were possessed by the major powers during World War II, althongh they were never employed in warfare. 

The carbamate and OP insecticides and the organophosphorous nerve gases soman, sarin, and tabun all act as anticholinesterases, and most of their toxicity is attributed to this property. The naturally occurring carbamate physostigmine, which has been used in medicine, is also an anticholinesterase. Some OP compounds can cause relatively long-lasting inhibition of the enzyme because of the phenomenon of... 

Other mnch more toxic componnds operating throngh specific biochemical mechanisms (e.g., OP anticholinesterases) cannot be modeled in this way. If... 

In contrast to the beneficial effects of treatment with oximes in cases of OP intoxication, reports in the literatnre suggest that treatment of poisoning with certain anticholinesterase carbamates with some oximes should be avoided because they may actually potentiate carbamate action. Other oximes decrease carbamate toxicity. The effects observed are, in general, correlated with changes in the rates of carbamylation and decarbamylation in the presence of the various oximes . ... 

The differences in the activity of A-esterases due to polymorphisms may have important effects on the toxicity of OP in humans who are occupationally or accidentally exposed. In this respect it was proposed that humans expressing lower activity of A-esterases could be more susceptible to toxic effects of OP and there were ideas that such individuals should not be exposed (Mackness, 1989). Hernandez et al (2004) have confirmed this hypothesis suggesting the association of paraoxonase phenotypes with susceptibility of humans to anticholinesterase pesticides toxicity. However, additional studies are needed to fully understand the effects of A-esterase polymorphism on the capacity of detoxification and toxicity of OPs. 

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