Organophosphorus compounds, toxic effects cholinesterase inhibition

This group of compounds is used as pesticides and nerve gases. The structure and therefore metabolism and potency varies. However, they all act in a similar manner. There are two toxic effects, cholinesterase inhibition and delayed neuropathy, but all OPs do not necessarily cause both. The cholinesterase inhibition results from the similarity between the organophosphorus compound and acetylcholine. The organophosphorus compound therefore acts as a pseudosubstrate but blocks the enzyme, in some cases, permanently. This is because the... 

With irreversible interactions, however, a single interaction will theoretically be sufficient. Furthermore, continuous or repeated exposure allows a cumulative effect dependent on the turnover of the toxin-receptor complex. An example of this is afforded by the organophosphorus compounds which inhibit cholinesterase enzymes (see Aldridge, 1996, and Chapter 7). This inhibition involves reaction with the active site of the enzyme which is often irreversible. Resynthesis of the enzyme is therefore a major factor governing the toxicity. Toxicity only occurs after a certain level of inhibition is achieved (around 50%). The irreversibility of the inhibition allows cumulative toxicity to occur after repeated exposures over an appropriate period of time relative to the enzyme resynthesis rate. 

An example of absolutely cumulative toxicity is afforded by tri-o-cresyl phosphate or TOCP (figure 2,9). This compound is a cholinesterase inhibitor and neurotoxin. In chickens, an acute dose of 30 mg/kg has a severe toxic effect, which is produced to the same extent by a dose of 1 (mg/kg)/day given for 30 days. This effect may of course be produced by accumulation of the compound in vivo to a threshold toxic level, or it may result from the accumulation of the effect, as it probably does in the case of TOCP. Thus, the inhibition of cholinesterase enzymes by organophosphorus compounds may... 

Pharmacodynamic-based toxic effects are those where there is altered responsiveness of the target site perhaps due to variations in the receptor. For example, individual variation in the response to digitoxin means that some patients suffer toxic effects after a therapeutic dose (see below Chapter 7). The inhibition of enzymes, blockade of receptors or changes in membrane permeability which underlie these types of effects often rely on reversible interactions. These are dependent on the concentration of the toxic compound at the site of action, and possibly the concentration of an endogenous substrate if competitive inhibition is involved. Therefore, with the loss of the toxic compound from the body, by the processes of metabolism and excretion, the concentration at the site of action falls and the normal function of the receptor or enzyme returns. This is in direct contrast to the type of toxic effect in which a cellular structure or macromolecule is permanently damaged, altered or destroyed by a toxic compound. In some cases, however, irreversible inhibition of an enzyme may occur, which if not fatal for the organism will require the synthesis of new enzyme, as is the case with organophosphorus compounds which inhibit cholinesterases. 

At around the same time, a small circle of Nazi officials learned about the discovery of Soman, one of the most deadly nerve agents known to man, which stiU required further development. Unbeknown to Schrader and many others working in the chemical warfare field, Richard Kuhn, director of the Kaiser Wilhelm Institute for Medical Research in Heidelberg, and his team of scientists had been commissioned by the military to screen various organophosphorus compounds for their level of cholinesterase (ChE) inhibition, and had discovered Soman in the process. When inhaled. Soman turned out to be twice as toxic as Sarin, was able to penetrate through the skin, and quickly affected the central nervous system. Because it inhibited cholinesterase very rapidly, the effective use of antidotes such as atropine was considerably reduced. Experiments on dogs and apes at Gross laboratory in Elberfeld quickly established the enormous toxicity of the new substance. 

The mechanism by which pesticides exert their toxic effects on mammals has been characterized for only a few groups of compounds [17,18]. For example, the mechanism for organophosphorus and carbamate insecticides involves inhibition of cholinesterase also, nitrophenols and higher chlorinated phenols are inhibitors for oxidative phosphorylation [10]. Fat-soluble substances (e.g., organochlorines such as DDT, HCH, and other persistent substances) accumulate in the body and, when stored in fatty tissues, cannot be... 

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