Oxime reactivation

Hansen ME, Wilson BW. 1999. Oxime reactivation of RBC acetylcholinesterases for biomonitoring. Arch Environ Contam Toxicol 37 283-289. 

TABLE 11. Oxime reactivities and formation 0X31. 4-XPnCH=NOH, X, IO Kthih (mol- ) ... 

TABLE 12. Results of correlations of oxime reactivities and formation ... 

Although the major research and development effort on oxime reactivators has focused on the positively charged pyridinium ring, the poor ability of the charged oximes to cross the blood-brain barrier (BBB) has prompted several studies on noncharged aliphatic oximes in an effort to increase reactivation of OP-inhibited AChE in the central nervous system. The most smdied noncharged oximes are mono isonitrosoacetone (MINA, 44) and diacetyl monoxime (DAM, 45) " . 

The effect on oximate reactivity of adding DMSO to an aqueous medium was first investigated by the authors in the 1980s . While in the first study a leveling effect on reactivity was observed when the DMSO content reached ca 50 mol%, in the subsequent study, increasing the DMSO content to 90 mol%, a maximum in the a-effect could be readily discerned, i.e. bell-shaped behavior. ... 

Oxime reactivators (R-CH N0H) are weak acids that partly Ionize at biologic pH. This property allows them to function as nucleophiles and displace organophosphate moieties from inhibited acetylcholinesterase. It also makes them vulnerable to decomposition by other mechanisms in the body. 

In another investigation, irreversible inhibition of enzyme activity was prevented by coincubation with reversible agents that either sterically block (edrophonium and decamethonium) or alio sterically modify (propidium) the acetylcholine site (Barnett and Rosenberry, 1977). Enzyme activity was not regenerated by incubation with oxime reactivators therefore, the mechanism of irreversible inhibition does not appear to involve acylation of the active site serine. 

Ashani, Y., Bhattacharjee, A.K., Leader, H., Saxena, A., Doctor, B.P. (2003). Inhibition of cholinesterases with cationic phos-phonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators. Biochem. Pharmacol. 66 191-202. 

Clement, J.G. (1992). Central actions of acetylcholinesterase oxime reactivators. Toxicol. Appl. Pharmacol. 112 104-9. 

Luo, C., Saxena, A., Smith, M., Garcia, G., Radic, Z., Taylor, P., Doctor, B.P. (1999). Phosphoryl oxime inhibition of acetylcholinesterase during oxime reactivation is prevented by edrophonium. Biochemistry 38 9937-47. 

Lorke, D.E., Hasan, M.Y., Arafat, K., Kuca, K., Musilek, K., Schmitt, A., Petroianu, G.A. (2008a). In vitro oxime reactivation of red blood cell acetylcholinesterase inhibitied by diisopropyl-fluorophosphate (DFP). J. Appl. Toxicol. 28 422-9. 

Patocka, J., Cabal, J., Kuca, K., Jun, D. (2005). Oxime reactivation of acetylcholinesterase inhibited by toxic phosphorus esters in vitro kinetics and thermodynamics. J. Appl Biomed. 2 91-9. 

Yang, G.Y., Oh, K.A., Park, N.J., Jung, Y.S. (2007). New oxime reactivators connected with CH20(CH2) 0CH2 linker and their reactivation potency for organophosphorus agents-inhibited acetylcholinesterase. Bioorg. Med. Chem. 15 7704-10. 

Wong, L., Radic, Z., Bruggemann, R.J., Hosea, N., Berman, H.A., Taylor, P. (2000). Mechanism of oxime reactivation of acetylcholinesterase analyzed by chirality and mutagenesis. Biochemistry 39 5750-7. 

In addition to providing hydroxy (alkoxy) amines, the reaction of oximes" or oxime ethers " with or-ganometallic reagents can generate additional products. The propensity for proton abstraction a to the carbon-nitrogen double bond, the existence of mixtures of ( )- and (Z)-oxime isomers, the lability of the nitrogen-oxygen bond coupled with the poor oxime reactivity all contribute to the variability of this reaction. 

The mechanism of action of oxime reactivation involves transfer of the substituted phosphate or phosphonate residue from the catalytic site of the... 

Red blood cell enzyme activity returns at the rate of red blood cell turnover, which is 1% per day. Tissue and plasma activities return with synthesis of new enzymes. The rates of return of these enzymes are not identical. However, the nerve agent can be removed from the enzymes. This removal is called reactivation, which can be accomplished therapeutically by the use of oximes prior to aging. Aging is the biochemical process by which the agent-enzyme complex becomes refractory to oxime reactivation. The toxicity of nerve agents may include direct action on nicotine acetylcholine receptors (skeletal muscle and ganglia) as well as on muscarinic acetylcholine receptors and the central nervous system. 

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