Sarin binding

Some very interesting results on the prophylaxis of sarin poisoning with DAM in normal and TOCP-pretreated rats are reported by Myers (1959). The author observed that with DAM prophylaxis the LD50 of sarin in the atropinized TOCP-pretreated rats was only one-seventeenth of LD50 in the atropinized normal rats. This may be regarded as a consequence of sarin binding to plasma CarbE in the normal rats, since any direct reaction between sarin and the prophylactic administered DAM should be similar in the normal and TOCP-pretreated animals. 

Not all toxic organophosphoms compounds have uses beneficial to humans. Sarin is an extremely toxic nerve gas that is lethal to humans. In March 1995 this substance was released in a terrorist attack on a Japanese subway, resulting in several deaths and many serious injuries. Sarin and related nerve gases bind an amino acid in the enzyme responsible for muscle action. When this enzyme is deactivated, muscles contract but cannot relax. Even a small dose can be lethal if the nerve gas reaches the muscles of the heart. 

Also the reaction pathways of Sarin decomposition catalyzed by selected forms of MgO were investigated [38]. In the case of the decomposition on the nonhydroxylated MgO surface, the removal of fluorine from Sarin was modeled. Fluorine was transferred from Sarin into binding distance with the Mg atom of the MgO surface (Fig. 13.9). It was revealed that such a structure provides a reliable model for the reaction mechanism. A two-step reaction mechanism was assumed. In the first step, Sarin creates a stable adsorbed complex with MgO through three chemical bonds with the MgO surface (the Al-GB model). It is expected that the transfer of the fluorine atom to the surface of MgO is accompanied by a change in the conformation of Sarin. In the second step, the bond between P and F is broken (the Al(t)-GB model) the fluorine atom is transferred to the Mg atom of the surface and the remaining part of Sarin adopts the most energetically favorable conformation (the Al(f)-GB model). 

Sarin and soman have been shown to bind to a tyrosine residue present in a blood protein (51). The precise site of this residue has not yet been confirmed but it is associated with the albumin fraction. An LC/ESI/MS/MS (triple quadrupole) method was developed for its detection after digestion of the albumin fraction with Pronase and clean up on a C18 SPE (solid-phase extraction) cartridge. A... 

Grigoryan, H., Schopfer, L.M., Thompson, C.M., Terry, A.V., Masson, P., Lockridge, O. (2008). Mass spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin a potential mechanism of long term toxicity by organophos-phoms agents. Chem. Biol. Interact. April 22. (Epub ahead of print)... 

Sarin was involved in terrorist attacks in Japan (Okumura et al, 2003 Okudera, 2002). The increase in sympathetic and parasympathetic tone results in tachycardia, ST-segment modulation (Abraham et al, 2001), and arrhythmia. Inhibition of cholinesterase within the neuroeffector junction also affects nerve impulse transmission by direct action. Direct action on muscarinic or nicotinic ACh receptors (Somani et al, 1992) is observed when the blood level of sarin exceeds the micromolar level. Sarin inhibits RBC-AChE 80-100% as well as plasma-BChE between 30 and 50% (Grob and Harvey, 1958). It also binds to aliesterase, an enzyme that contributes to ester-link hydrolysis. 

It was shown that tabun, sarin, soman, and VX bind to the muscarinic receptor subtype m2, leading to the assumption... 

FIGURE 51.4. Hypothetical bound GB vs free sarin concentrations for saturable AChE binding, and linear nonspecific binding. The AChE binding has a higher initial slope, so it will dominate in a competitive situation at low doses (A), but is saturable and so will eventually be swamped by the nonspecific binding at higher doses (B). 

In addition, due to the reversibility of the binding reaction of sarin and soman to CarbE, it appears that CarbEs are involved in metabolic detoxification of these agents to their corresponding nontoxic metabolites isopropyl methylphosphonic acid (IMPA) and pinacolyl methylphosphonic acid (PMPA) (Jokanovic et al, 1996). 

While the biological role of ChE is presently unelear, it is known that soman, sarin, tabun, and VX bind to ChE, without any apparent toxic effects, decreasing the amount of free agents available for inhibition of AChE in the eentral nervous system and erythrocytes. Pretreatment with human... 

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