Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 3 (2005), No 2, p 91-99




Oxime reactivation of acetylcholinesterase inhibited by toxic phosporus ester: in vitro kinetics and thermodynamics

Jiri Patocka, Jiri Cabal, Kamil Kuca, Daniel Jun

Address: Department of Toxicology, School of Military Health Sciences, University of Defense, Hradec Kralove, Czech Republic
kucakam@pmfhk.cz

Received 1st November 2006.
Revised 19th December 2006.
Published online 12th February 2007.

Full text article (pdf)

SUMMARY
Owing to the threat of organophosphate exposures, not only to pesticides but also to nerve agents, it is very important to know the whole process of organophosphates-inhibited acetylcholinesterase (AChE, EC 3.1.1.7) reactivation. Although current antidotes against organophosphorus intoxications consist also of prophylactics, AChE reactivators are still needed especially in the case of intoxications with high doses of organophosphates, for which prophylactic treatment is not effective. For this reason, new AChE reactivators are still being developed. Our work summarizes accurately the whole reactivation process, and offers some help for scientists who are interested in the area of AChE reactivation.

KEY WORDS
acetylcholinesterase; reactivation; nerve agents; kinetics; thermodynamics; oximes


REFERENCES
Aldridge WN, Reiner E: Acetylcholinesterase. Two types of inhibition by an organophosphorus compound: one the formation of phosphorylated enzyme and the other analogous to inhibition by substrate. Biochem J 115:147-162, 1969.
[PubMed]

Bajgar J: Organophosphates/nerve agents poisoning: mechanism of action, diagnosis, prophylaxis and treatment. Adv Clin Chem 38:151-216, 2004.
[CrossRef]

Bajgar J: Prophylaxis against organophosphorus poisoning. J Med Chem Def 1:1-16, 2004.

Berman HA, Leonard K: Ligand exclusion on acetylcholinesterase. Biochemistry 29:10640-10649, 1990.
[CrossRef] [PubMed]

Bourne Y, Taylor P, Radic Z, Marchot P: Structural insight into ligand interactions at the acetylcholinesterase peripheral anionic site. EMBO J 22:1-12, 2003.
[CrossRef] [PubMed]

Cabal J: Comparison of dialkylamidofluorphosphate acid esters features with other fluoroorganophosphates. Voj Zdrav Listy 61:215-221, 1992 (io Czech).

Cabal J, Hampl F, Liska F et al.: Hydrates of quaternary ammonium aldehydes as potential reactivators of sarin-inhibited acetylcholinesterase. 63:1021-1030, 1998.

Cabal J, Kuca K, Kassa J: Specification of the structure of oximes able to reactivate tabun inhibited acetylcholinesterase. Pharmacol Toxicol 95:81-86, 2004.
[CrossRef] [PubMed]

Childs AF, Davies DR, Green AL, Rutland JP: The reactivation by oximes and hydroxamic acids of cholinesterase inhibited by organo-phosphorus compounds. Br J Pharmacol 10:462-465, 1955.

Davies DR, Green AL: The kinetics of reactivation, by oximes, of cholinesterase inhibited by organophosphorus compounds. Biochem J 63:529-535, 1956.
[PubMed]

Dohnal V, Kuca K, Havel J, Cabal J: Prediction of new efficient cyclosarin-inhibited acetylcholinesterase reactivators structures using method of arteficial neural networks. Chem Listy 97:1201-1202, 2003.

Harel M, Schalk I, Ehret-Sabatier L et al.: Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 90:9031-9035, 1993.
[CrossRef]

Heath DF: Organophosphorus Poisons: Anticholinesterases and Related Compounds Pergamon Press, Oxford 1961, pp.403.

Hobbiger F, O'Sullivan DG, Sadler PW: New potent reactivators of acetylcholinesterase inhibited by tetraethyl pyrophosphate. Nature 182:1498-1499, 1958.
[CrossRef] [PubMed]

Kassa J, Cabal J: A comparison of the efficacy of acetylcholine reactivators against cyclohexyl methylphosphonofluoridate (GF agent) by in vitro and in vivo methods. Pharmacol Toxicol 84:41-45, 1999.
[PubMed]

Kuca K, Bielavsky J, Cabal J, Bielavska M.: Synthesis of a potential reactivator of acetylcholinesterase 1-(4- hydroxyiminomethylpyridinium)-3- (carbamoylpyridinium)-propane dibromide. Tetrahedron Lett 44:3123-3125, 2003a.
[CrossRef]

Kuca K, Bielavsky J, Cabal J, Kassa J: Synthesis of a new reactivator of tabun inhibited acetylcholinesterase. Bioorg Med Chem Lett 13:3545-3547, 2003b.
[CrossRef]

Kuca K, Patocka J, Cabal J: Reactivation of organophosphate inhibited acetylcholinesterase activity by alpha,omega-bis-(4- hydroxyiminomethylpyridinium)alkanes in vitro. J Appl Biomed 1:207-211, 2003c.
[JAB]

Kuca K, Picha J, Cabal J, Liska F: Synthesis of the three monopyridinium oximes and evaluation of their potency to reactivate acetylcholinesterase inhibited by nerve agents. J Appl Biomed 2:51-56, 2004.
[JAB]

Kuca K, Kassa J: A Comparison of the ability of a new bispyridinium oxime - 1-(4- hydroxyiminomethylpyridinium)-4-(4- carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agentinhibited rat brain acetylcholinesterase by in vitro methods. J Enzyme Inhib Med Chem 18:529-535, 2003.
[CrossRef] [PubMed]

Kuca K, Patocka J: Reactivation of cyclosarin-inhibited rat brain acetylcholinesterase by pyridinium-oximes. J Enzyme Inhib Med Chem 19:39-43, 2004.
[CrossRef] [PubMed]

Leader H, Vincze A, Manisterski B et al.: Characterization of O,O-diethylphosphoryl oximes as inhibitors of cholinesterases and substrates of phosphotriesterases. Biochem Pharmacol 58:503-15, 1999.
[CrossRef]

Mager PP: Quantitative structure-reactivity and structure-toxicity relationships of reactivators ofager. QSAR applied to aging of phosphylated acetylcholinesterase. Pharmazie 36:450-451, 1981.
[PubMed]

Mager PP: QSAR applied to aging of phosphylated acetylcholinesterase. Pharmazie 38:271-272, 1983.
[PubMed]

Mager PP, Weber A: Structural bioinformatics and QSAR analysis applied to the acetylcholinesterase and bispyridinium aldoximes. Drug Des Dis 18:127-150, 1983.
[CrossRef] [PubMed]

Millard CB, Kryger G, Ordentlich A et al.: Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level. Biochemistry 38:7032-7039, 1999.
[CrossRef] [PubMed]

O'Brien RD: Toxic Phosphorus Esters. Academic Press, New York, London 1960, pp. 74.

Pang YP, Kollmeyer TM, Hong F et al.: Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem Biol 10:491-502, 2003.
[CrossRef]

Patocka J: Reactivation of isopropyl-methylphosphonylated rat brain acetylcholinesterase by oximes. Coll Czech Chem Commun 37:899-906, 1972a.

Patocka J: Reactivation of isopropyl-methylphosphonylated acetylcholinesterase by alpha,omega-bis-(4-hydroxyiminomethylpyridinium)-2- trans-butene dibromide. The effect of temperature. Biochem Pharmacol 21:3192-3196, 1972b.
[CrossRef]

Patocka J, Bielavsky J: Afinity of bis-quaternary pyridiniumaldoximes for the active centre of intact and isopropylmethylphosphonylated acetylcholinesterase. Coll Czech Chem Commun 37:2110-2116, 1972a.

Patocka J, Bielavsky J: Reactivation of isopropyl-methylphosphonylated acetylcholinesterase by alpha,omega-bis-(4-hydroxyiminomethylpyridinium)-2- trans-butene dibromide - The effect of pH. Biochem Pharmacol 21:742-745, 1972b.
[CrossRef]

Patocka J, Kuca K, Jun D: Acetylcholinesterase: crucial enzyme of human body. Acta Medica (Hradec Kralove) 47:215-230, 2004.

Schumacher M, Camp S, Maulet Y et al.: Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence. Nature 319:407-409, 1986.
[CrossRef] [PubMed]

Sussman JL, Harel M, Frolow F et al.: Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science 253:872-879, 1991.
[CrossRef] [PubMed]

Wilson IB, Ginsburg S: A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase. Biochim Biophys Acta 18:168-170, 1955.
[CrossRef]
CITED

Hackenberger BK, Velki M, Stepic S, Hackenberger DK. The effect of formalin on acetylcholinesterase and catalase activities, and on the concentration of oximes, in the earthworm species Eisenia andrei. Eur J Soil Biol. 50: 137-143, 2012.

Kozaci N, Gokel Y, Acikalin A, Icme F. Comparison of single-dose pralidoxime and pralidoxime infusions for the treatment of organophosphate poisoning. Turkyie Klinikleri Tip Bilimleri Dergisi. 32: 472-477, 2012.

Kesharwani MK, Bandyopadhyay T, Ganguly B. Probing O-dealkylation and deamination aging processes in tabun-conjugated AChE: a computational study. Theor Chem Acc. 131, art. no. 1175, 2012.

Bajgar J, Kassa J, Pohanka M, Zdarova Karasova J, Novotny L, Fusek J, Blaha V. Inhibition of blood and tissue cholinesterases by soman in guinea pigs in vivo. J Appl Biomed. 9: 35-41, 2011.

Wang ZY, Zhang K, Zhao J, Liu XY, Xing BS. Adsorption and inhibition of butyrylcholinesterase by different engineered nanoparticles. Chemosphere. 79: 86-92, 2010.

Suganthy N, Karutha Pandian S, Pandima Devi K. Neuroprotective effect of seaweeds inhabiting South Indian coastal area (Hare Island, Gulf of Mannar Marine Biosphere Reserve): Cholinesterase inhibitory effect of Hypnea valentiae and Ulva reticulata. Neurosci Lett. 468: 216-219, 2010.

Kuca K, Gupta RC, Musilek K, Jun D, Pohanka M. In vitro identification of novel acetylcholinesterase reactivators. Toxin Reviews. 28: 238-244, 2009.

Bajgar J, Jun D, Kuca K, Fusek J, Zdarova Karasova J, Kassa J, Cabal J, Blaha V. Inhibition of blood cholinesterases by nerve agents in vitro. J Appl Biomed. 7: 201-206, 2009.

Jun D, Paar M, Binder J, Marek J, Pohanka M, Stodulka P, Kuca K. Preparation and in vitro evaluation of monoquaternary inhibitors of brain cholinesterases. Lett Organic Chem. 6: 500-503, 2009.

Kuz'min VE, Muratov EN, Artemenko AG, Varlamova EV, Gorb L, Wang J, Leszczynski J. Consensus QSAR Modeling of Phosphor-Containing Chiral ACNE Inhibitors. QSAR Comb Sci. 28: 664-677, 2009.

Zdarova Karasova J, Kassa J, Musilek K, Pohanka M, Novotny L, Kuca K. Effect of seven newly synthesized and currently available oxime cholinesterase reactivators on cyclosarin-intoxicated rats. Int J Mol Sci. 10: 3065-3075, 2009.

Natarajan S, Shanmugiahthevar KP, Kasi PD. Cholinesterase inhibitors from Sargassum and Gracilaria gracilis: Seaweeds inhabiting South Indian coastal areas (Hare Island, Gulf of Mannar). Nat Prod Res. 23: 355-369, 2009.

Tiwari S, Kolay S, Ghosh KK, Kuca K, Marek J. Kinetic study of the reactions of p-Nitrophenyl acetate and p-Nitrophenyl benzoate with oximate nucleophiles. Int J Chem Kinet. 41: 57-64, 2009.

Pohanka M, Jun D, Kalasz H, Kuca K. Cholinesterase biosensor construction - A review. Protein Pept Lett. 15: 795-798, 2008.

Kuca K, Stodulka P, Hrabinova M, Hanusova P, Jun D, Dolezal B. Preparation of oxime HI-6 (dichloride and dimethanesulphonate)-antidote against nerve agents. Defence Sci J. 58: 399-404, 2008.

Rao JV. Brain acetylcholinesterase activity as a potential biomarker for the rapid assessment of chlorpyrifos toxicity in a euryhaline fish, Oreochromis mossambicus. Environ Bioindic. 3: 11-22, 2008.

Kuca K, Jun D, Bajgar J. Structural factors influencing potency of currently used acetylc holineste rase reactivators for treatment of cyclosarin intoxications. Curr Pharm Des. 13: 3445-3452, 2007.

Musilek K, Holas O, Kuca K, Jun D, Dohnal V, Dolezal M. Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase. J Enzyme Inhib Med Chem. 22: 425-432, 2007.

Kassa J, Karasova J. The evaluation of the neuroprotective effects of bispyridinium oximes in Tabun-poisoned rats. J Toxicol Environ Health Part A. 70: 1556-1567, 2007.

Kuca K, Racakova V, Jun D. Structure-activity relationships for in vitro oxime reactivation of chlorpyrifos-inhibited acetylcholinesterase. Chem Papers. 61: 256-261, 2007.

Wang J, Gu J, Leszczynski J, Feliks M, Sokalski WA. Oxime-induced reactivation of sarin-inhibited AChE: A theoretical mechanisms study. J Phys Chem B. 111: 2404-2408, 2007.

Kuca K, Jun D, Musilek K, Bajgar J. Reactivators of tabun-inhibited acetylcholinesterase: structure-biologicak activity relationship. Front Drug Des Discovery. 3: 381-394, 2007.

Bajgar J, Fusek J, Bartosova L, Jun D, Kuca K. Evaluation of reactivation test in anaesthetized dogs with experimental intoxication with nerve agents. J Appl Toxicol. 26: 439-443, 2006.

Kuca K, Cabal J, Jun D, Hrabinova M. In vitro evaluation of acetylcholinesterase reactivators as potential antidotes against tabun nerve agent poisonings. Drug Chem Toxicol. 29: 443-449, 2006.

Kuca K, Jun D, Kirn TH, Cabal J, Jung YS. In vitro evaluation of new acetylcholinesterase reactivators as casual antidotes against tabun and cyclosarin. Bull KOREAN Chem Soc. 27: 395-398, 2006.

Kuca K, Jun D, Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini-Rev Med Chem. 6: 269-277, 2006.

Kuca K, Cabal J, Jun D, Hrabinova M. In vitro evaluation of acetylcholinesterase reactivators as potential antidotes against tabun nerve agent poisonings. Drug Chem Toxicol. 29: 443-449, 2006.

Kassa J, Kunesova G. Comparison of the neuroprotective effects of the newly developed oximes (K027, K048) with trimedoxime in tabun-poisoned rats. J Appl Biomed. 4: 123-134, 2006.

Kuca K, Jun D, Kim T-H, Cabal J, Jung Y-S. In vitro evaluation of new acetylcholinesterase reactivators as casual antidotes against tabun and cyclosarin. Bull Korean Chem Soc. 27: 395-398, 2006.

Kuca K, Jun D, Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini-Rev Med Chem. 6: 269-277, 2006.

Kozaci N. Organofosfat zehirlenmelerinde pralidoksimin farkli doz uygulama sekillerinin etkinligi ve yan etkilerinin klinik karsilastirilmasi. Thesis. Cukurova Universitesi, Adana 50 p, 2006.

Kuca K, Cabal J, Musilek K, Jun D, Bajgar J. Effective bisquaternary reactivators of tabun-inhibited AChE. J Appl Toxicol. 25: 491-495, 2005.

Davidova L, Maxnerova I, Handschuhova S, Patocka J. Atropin a jeho misto v soucasne medicine. Kontakt. 7: 349-352, 2005.

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