Soman detoxification

S. H. Stem, G. Valdai, S. Lyngaas, E. Odden, D. Malthe-Sprenssen, F. Fonnum, The Mechanism of Soman Detoxification in Perfused Rat Liver , Biochem. Pharmacol. 1983, 32, 1941-1943. 

As anhydrides, such compounds are subject to spontaneous hydrolysis, which may contribute to detoxification [160]. Thus, soman hydrolysis at pH 7.5 and 37° occurs with a rate constant of 0.003 - 0.004 min-1 and an activation energy of ca. 55 kJ mol 1 [161]. However, most of the published data refer to enzymatic hydrolysis. Enzymes hydrolyzing P-X anhydride bonds are now known as organophosphorus acid anhydrolases (OPA anhydrolases) classified as EC 3.1.8.2 (also known as diisopropyl-fluorophosphatase, DFPase, tabunase, somanase), an activity related to EC 3.1.8.1 (aryldialkyl-phosphatase, paraoxonase, A-esterase) and formerly classified as EC 3.8.2.1 [64] [65] [69], Much public information on these enzymes can be found in [106],... 

A recent study has revisited the reactivity of oximate nucleophiles toward detoxification of sarin, soman and DFP, using a fluoride-selective electrode to kinetically monitor decomposition of the neurotoxin . Results are shown in Table 1. 

Maxwell, D.M., D.E. Lenz, W.A. Groff, A. Kaminskis and H.L. Eroehlich. 1987a. The effects of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats. Toxicol. Appl. Pharmacol. 88 66-76. 

Sarin and its corresponding nontoxic hydrolysis products (IMPA, and additional methyl phosphonic acids) are predominantly eliminated via the kidneys which are thus more important for detoxification than the liver (Little et al, 1986 Waser and Streichenberg, 1988). Urinary excretion happens quite rapidly as demonstrated for single dose s.c. application of sarin, cyclosarin, and soman to rats (Shih et al, 1994). The terminal elimination half-life was found to be 3.7 =E 0.1 h for sarin and 9.9 0.8 h for cyclosarin. In contrast soman showed a biphasic elimination with terminal half-fives of about 18.5 h and 3.6 h (Shih et al, 1994). Maximum peak levels of sarin metabolites in urine were detected 10-18 h after exposure (Minami et al, 1997) and after 2 days hydrolyzed sarin metabolites had been excreted nearly quantitatively (Shih et al, 1994). In contrast, even at 5 days post-exposure soman metabolite recovery was only 62% (Shih et al, 1994). Excretion of soman from blood, fiver, and kidney compartments following cfiemical and enzymatic hydrolysis is considered a first-order elimination process (Sweeney et al, 2006). 

Nordgren, I., Lundgren, G., Puu, G., Holmstedt, B. (1984). Stereoselectivity of enzymes involved in toxicity and detoxification of soman. Arch. Toxicol 55 70-5. 

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). 

One of the important proofs which support the significance of detoxification reactions of nerve agents in the body was presented by Fonnum and Sterri (1981) who reported that only 5% of LD50 of soman in rats or about 5 P-g/kg reacts with AChE causing acute toxic effects, while the remaining 95% undergoes various metabolic reactions. 

FIGURE 52.1. Metabolic detoxification of warfare nerve agents tabun, sarin, soman, and VX in mammals in vivo. Chemical names of metabolites are EDMPA - ethyl dimethylaminophosphoric acid, IMPA - isopropyl methylphosphonic acid, PMPA - pinacolyl methyl-phosphonic acid, EMPA - ethyl methylphosphonic acid, and MPA - methylphosphonic acid. 

Li et al. (2008) have shown that soman covalently binds to albumin at tyrosine 411. The adduct is stable (/i/2 = 20 days). However, though the concentration of albumin in plasma is very high, its reactivity with soman is too slow to play a major role in detoxification of the agent. The authors concluded that soman-albumin adducts could be usefid for the diagnosis of soman exposure. Tarhoni et al. (2008) also found that OP pesticides covalently bind to albumin and that the adduct is stable for more than 7 days. 

Benschop, H.P., Konings, C.A.G., De Jong, L.PA. (1981). Gas chromatographic separation and identification of the four stereoisomers of 1,2,2-trimethylpropyl methylphosphono-fluoridate (soman). Stereospecificity of in vitro detoxification reactions. J. Am. Chem. Soc. 103 4260. 

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... 

Hoskin, F.C.G., G. Chettur, S. Mainer, and K.E. Steinmann. 1989. Soman hydrolysis and detoxification by a thermophilic bacterial enzyme. In Enzymes Hydrolyzing Organophosphorus Compounds, E. Reiner, F.C.G. Hoskin, and N.W. Aldridge, Eds. Ellis Horwood, Chichester, U.K., pp. 53-64. 

The elimination of VX deviates from that of soman. As observed in the toxicokinetic smdies, the elimination of VX proceeds much slower than that for the G-agents. In addition to the major detoxification route of VX, which leads to the formation of 0-ethyI methylphosphonic acid, it cannot be excluded that toxic metabolites will be formed. Possible toxic metabolites are the deal-kylated form of VX or desethyl-VX and the N-oxide of VX. Neither metabolite has been found in blood samples taken for toxicokinetic experiments. In vitro experiments, in which high concentrations of VX (10 p,g/mL) were incubated in plasma or fiver homogenate, did not yield any of these toxic metabolites either. However, desethyl-VX could be detected in reasonable amounts when plasma was derived from blood that was drawn in mbes with EDTA as anticoagulant. EDTA binds metal ions that are essential for the enzymatic hydrolysis of VX, which leads to the formation of EMPA. When that route is inhibited, the formation of desethyl-VX may increase. ... 

Clement JG. Importance of aliesterase as a detoxification mechanism for soman (pinacolyl methylphosphono-fiuoridate) in mice. Biochem Pharmacol, 1984 33 3807-3811. 

Harris, L., Broomfield, C., Adams, N., and Stitcher, D., Detoxification of soman and O-cyclopentyl S-diethylaminoethyl methylphosphonothioate in vivo, Proc. West Pharmacol Soc., 27, 315, 1984. 

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