Soman isomers

This large selectivity correlates with toxicity in vivo where the P(+) isomers are virtually non-toxic. There is little differentiation of the C(-) and C(+) isomers of soman. As discussed in Section XI, the enantioselective interaction of soman isomers with other esterases also effects toxicity in vivo. Tabun and show less enantioselectivity in... 

Isomers of soman were separated by GC on a Chirasil-L-Val column but lacked baseline separation (Benschop et al, 1981, 1985 Li et al., 2003). In contrast, (+)-sarin and (—)-sarin could be completely separated by the same column (Benschop and de Jong, 2001). A recent study presented a modified method using a Chiraldex y-cyclo-dextrin trifluoroacetyl GC-column coupled to an electron impact (EI)-MS which enabled sufficient baseline separation of all four stereoisomers of soman (Smith and Schlager, 1996 Yeung et al, 2008). 

Benschop and De Jong, 1988). In the case of toxicokinetic studies, it is important to differentiate between the two isomers because it is essential to know which isomer is stiU present in the circulation. Chiral gas chromatography can fulfill this requirement for G-agents like sarin and soman. Soman has two asymmetric atoms, phosphorus and carbon in the pinacolyl group. Therefore, the compound consists of four different stereoisomers. 

Nerve agents are hydrolyzed by the enzyme organophosphate (OP) hydrolase. The hydrolysis of GB, soman (GD), tabun (GA), and diisopropyl flu-orophosphate occurs at approximately the same rate. The isomers of the asymmetric OPs may differ in overall toxicity, rate of aging, rate of cholinesterase inhibition, and rate of detoxification. The rates of detoxification differ for different animal species and routes of administration. The onset of effects from nerve agents depends on the route, duration, and amount of exposure. The effects can occur within seconds to several minutes after exposure. There is no... 

Electric eel AChE (pH 7.5, 25°C) for soman stereo-isomers bovine erythrocyte AChE for sarin and VX stereo-isomers (pH 7.7, 25°C). 

Based on the earlier-mentioned ratio of the C(- -)P(—) and C(—)P(—)-isomers of soman it would be expected that the AUC of the C(- -)P(—)-isomer is 20% higher than that of the C(—)P(—)-isomer. Instead, the AUC of C(+)P(—)-isomer is often equal to or even lower than C(—)P(—)-isomer. This outcome can be explained by taking into consideration the difference in binding rate constant with CaE, which is 30-fold higher for the C(+)P(—)-isomer. The relative effect of differential binding of C(- -)P(—)- and C(—)P(—)-soman with CaE becomes more pronounced at lower doses of soman, because the elimination route of binding to a finite amount of CaE is relatively more... 

The rapid decrease of soman levels in blood after i.v. administration or respiratory exposure is due to three processes, that is, distribution to various tissues, spontaneous or enzymatic hydrolysis, and covalent binding. It has been established that the toxic C( + )P( )-isomers react rapidly with covalent binding sites. The less toxic C( )P(- -)-isomers are hydrolyzed several orders of magnitude faster than the C( + )P( )-isomers. The low toxicity of the C( + )P(+)-isomers is primarily due to a low intrinsic reactivity toward AChE and rapid hydrolysis. 

In order to study the effect of the scavenger we compared the toxicokinetic data of the HuBuChE-pretreated and nonpretreated animals. Eigure 5.15 shows the concentration-time curves of C(—)P(—)-soman after i.v. administration of soman in naive and HuBuChE-pretreated animals. Evidently, the concentrations of C(—)P(—)-soman in HuBuChE-pretreated animals are much lower than those in naive animals. This effect of the scavenger is also clearly reflected in the values of the AUC shown in Table 5.5. The difference in AUC of the P(—)-isomers between naive and HuBuChE-pretreated animals is 65.9 — 2.9 = 63ng min mL , which is equal to 0.34nmol min niL. The period of time that acutely toxic levels of soman exist is reduced from 40 to 1 min. 

After one injection of soman only the C(—)P(—)-isomer of soman could be detected in the HuBuChE-pretreated guinea pigs. The C(+)P(—)-isomer had completely disappeared from the blood stream. In a qualitative sense, this result was expected in view of the higher binding constant of C(+)P(—) with BuChE compared with the binding constant of the C(—)P(—)-isomer with BuChE. 

FIGURE 8.3 Comparative reactivation kinetics of soman-inhibited human butyrylcholinesterase single mutant G117H ( ) and double mutant G117H/E197Q ( ). Note that the recovery rate of the double mutant is very fast (with reaction rates of 77,000 and 128,000/min for the PsCs and PsCr isomers of soman, respectively), whereas the single mutant does not recover measurably. The insert shows that reactivation of the double mutant... 

The first evidence for enantioselectivity in the reaction of organophosphorus compounds with AChE was reported by Michel who noted a biphasic inhibition on incubation of AChE with racemic sarin. Shortly afterwards, Aaron et reported enantioselective AChE inhibitory activity for the resolved isomers of O-ethyl S-(2-ethylthioethyl) ethylphosphonothionate. Subsequent isolation, or partial resolution, of the enantiomers of sarin, soman, tabun and VX has shown that there is a very large enantioselectivity for cholinesterase inhibition k, ratios 10 -l 0 ) between the P(-) and P(+) isomers of sarin and soman, shown in Table 12. 

Organophosphoms chemical agents are often mixtures of isomers. It is possible to separate, chromatographicaUy, four stereoisomers of soman and enantiomers of sarin and tabun using short capillary columns packed with chiral... 

Despite these differentiations, rather low catalytic activity of recombinant human PONl expressed in HEK cells occurred as a moderate stereoselective process characterized by preferred cleavage of fhe less toxic P(-l-)C(-l-)-enantiomer of soman (kcat 1,030mim ), which happens twice as fast as for fhe ofher fhree stereoisomers (Yeung et al., 2007, 2008 see Table 56.3). Nordgren et al. (1984) used an enzyme isolated from swine kidney, which fhey called "phosphoryl phosphafase," to incubate purified enanhomers of soman in vitro. Whereas fhe less toxic P(-l-)-isomers (RpSc- and RpRc-soman) were hydrolyzed very rapidly (ri/2 =... 

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