Soman detoxifying

Menger et al. synthesized a Ci4H29-attached copper(II) complex 3 that possessed a remarkable catalytic activity in the hydrolysis of diphenyl 4-nitrophenyl phosphate (DNP) and the nerve gas Soman (see Scheme 2) [21], When 3 was used in great excess (ca. 1.5 mM, which is more than the critical micelle concentration of 0.18 mM), the hydrolysis of DNP (0.04 mM) was more than 200 times faster than with an equivalent concentration of the nonmicellar homo-logue, the Cu2+-tetramethylethylenediamine complex 9, at 25°C and pH 6 (Scheme 4). The DNP half-life is calculated to be 17 sec with excess 1.5 mM 3 at 25°C and pH 6. The possible reasons for the rate acceleration with 3 were the enhanced electrophilicity of the micellized copper(II) ion or the acidity of the Cu2+-bound water and an intramolecular type of reaction due to the micellar formation. On the basis of the pH(6-8.3)-insensitive rates, Cu2+-OH species 3b (generated with pK3 < 6) was postulated to be an active catalytic species. In this study, the stability constants for 3 and 9 and the thermodynamic pvalue of the Cu2+-bound water for 3a —> 3b + H+ were not measured, probably because of complexity and/or instability of the metal compounds. Therefore, the question remains as to whether or not 3b is the only active species in the reaction solution. Despite the lack of a detailed reaction mechanism, 3 seems to be the best detoxifying reagent documented in the literature. 

Toxicity of organophosphates can be potentiated 15-20-fold in rats and mice by pretreatment with a metabolite of tri-O-cresylphosphate, CBDP (2-0-cresyl)-4H-l,3,2-benzodioxa-phosphorin-2-oxide), which is an irreversible inhibitor of CarbEs. In similar studies, tetraisopropylpyrophosphoramide (iso-OMPA), or mipafox, an organophosphate-irreversible inhibitor of CarbEs, potentiates three-to fivefold the toxicity of several OPs (soman, DFP, and methylparathion) and carbamates (carbofuran, aldicarb, propoxur, and carbaryl). Inhibition of CarbEs by CBDP, iso-OMPA, or mipafox pretreatment, particularly in plasma, liver, heart, brain, and skeletal muscles, is a major contributory factor in the potentiation of toxicity of organophosphates and carbamates. Thus, the toxicity of any drug, pesticide, or other type of agent that is normally detoxified by CarbEs, could be potentiated by pre-exposure to an organophosphorus or other carboxylesterase inhibitor. 

Chettur, G., J.J. DeFrank, B.J. Gallo, F.C.G. Hoskin, S. Mainer, F.M. Robbins, K.E. Steinmann, and J.E. Walker. 1988. Soman-hydrolyzing and -detoxifying properties of an enzyme from a therophilic bacterium. Fundam. Appl. Toxicol. 11 373-380. 

Hoskin, F.C.G. 1985. Inhibition of soman- and di-isopropylphosphorofluoridate (DFP)-detoxifying enzyme by mipafox. Biochem. Pharmacol. 34 2069-2072. 

The establishment of IDLH levels does not mean that exposure to lower levels of CWAs or most TICs is safe. Exposure to chemicals at concentrations much lower than the IDLH level for a long period will also be dangerous or even fatal. Although exposures to lower concentrations for a short period may not cause immediately observable effects or symptoms, toxicity effects may be cumulative. While some toxic substances (such as HCN) can be gradually detoxified naturally by human organs, many of them cause irreversible effects. The latter type of compound is commonly called refractory. Soman (or GD) and other refractory compounds must be handled with special care to avoid any exposure. 

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