Inactivation of acetylcholinesterase by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride

Molecular and Cellular Biochemistry - 2003
Lun-Yi Zang1, Hara P. Misra1
1Edward Via Virginia College of Osteopathic Medicine, Blacksburg, USA

Tóm tắt

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to reversibly inhibit the activity of acetylcholinesterase. The inactivation of the enzyme was detected by monitoring the accumulation of yellow color produced from the reaction between thiocholine and dithiobisnitrobenzoate ion. The kinetic parameter, K m for the substrate (acetylthiocholine), was found to be 0.216 mM and K i for MPTP inactivation of acetylcholinesterase was found to be 2.14 mM. The inactivation of enzyme by MPTP was found to be dose-dependent. It was found that MPTP is neither a substrate of AChE nor the time-dependent inactivator. The studies of reaction kinetics indicate the inactivation of AChE to be a linear mixed-type inhibition. The dilution assays indicate that MPTP is a reversible inhibitor for AChE. These data suggest that once MPTP enters the basal ganglia of the brain, it can inactivate the acetylcholinesterase enzyme and thereby increase the acetylcholine level in the basal ganglia of brain, leading to potential cell dysfunction. It appears that the nigrostriatal toxicity by MPTP leading to Parkinson's disease-like syndrome may, in part, be mediated via the acetylcholinesterase inactivation.

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Tài liệu tham khảo

Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979-980, 1983

Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ: A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compact of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80: 4546-4550, 1983

Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC: Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Nature (London) 311: 467-469, 1984

Langston JW, Irwin I, Langston EB, Forno LS: 1-methyl-4-phenylpyridinium ion (MPP+): Identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 48: 87-92, 1984

Chiba K, Trevor A, Castagnoli N: Metabolism of the neurotoxic amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120: 574-579, 1984

Chiba K, Peterson LA, Castagnoli KP, Trevor AJ, Castagnoli NE Jr: Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Drug Metab Dispos 13: 342-347, 1985

Gessner W, Bross A, Shen RS, Abell CW: Further insight into the mode of action of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). FEBS Lett 183: 345-348, 1985

Lewin R: Brain enzyme is the target of drug toxin: A chemical known as MPTP causes a Parkinson-like state in humans and monkeys; biochemical and autoradiographical studies are closing in on the mechanism. Science 225: 1460-1462, 1984

Youdim MBH, Finberg PM: New directions in monoamine oxidase A and B selective inhibitors and substrates. Biochem Pharmacol 41: 155-162, 1991

Krueger M, McKeown K, Ramsay R, Youngster SK, Singer TP: Mcchanism-based inactivation of monoamine oxidase A and B by tetrahydropyridines and dihydropyridines. Biochem J 268: 219-224, 1990

Burnhan WM: Drugs acting on the basal ganglia. In: Principles of Medical Pharmacology. B.C. Decker Inc., Toronto, Philadelphia, 1989, pp 198-202

Francis GS: Modulation of peripheral sympathetic nerve transmission. J Am Coll Cardiol 12: 250-254, 1988

Flattery KV, Spero L: Autonomic nervous system neurotransmitters. In: Principles of Medical Pharmacology. B.C. Decker Inc., Toronto, Philadelphia, 1989, pp 198-202

Ballinger JC, Levy-Serpier J, Debord J, Penicaut B: Acetylcholinesterase inhibition by two phosphoric 4-nitroanilides. J Enz Inhib 3: 211-217, 1990

Ellman GL, Courtney KD, Andres V Jr, Featherstone RM: A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol 7: 88-95, 1961

Ellman GL: Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70-77, 1959

Branchini BR, Lajiness E: Inactivation of acetylcholinesterase with a bretylium tosylate photoaffinity probe. Biochim Biophys Acta 884: 135-141, 1986

Dixon M, Webb E, Thorne CJR, Tipton KF: Enzyme inhibition and activation. In: Enzymes. Academic Press, New York, 1979, pp. 332-467

Ghag S, Wright A, Moudgil VK: Inactivation of rat brain acetylcholinesterase by pyridoxal 5′-phosphate. Biochim Biophys Acta 881: 30-37, 1986

Segel IH: Enzyme inhibition. In: Biochemical Calculations. John Wiley & Sons, Inc., 1976, pp 246-272

Vallette FM, Marsh DJ, Muller F, Massoulie J: Comparative affinity chromatography of acetylcholinesterase from five vertebrate species. J Chromatogr 257: 285-296, 1983

Das YT, Brown HD, Chattopadhyay SK: Microcalorimetric determination of binding sites of acetylcholinesterase. Biochim Biophys Acta 745: 107-110, 1983

Forberg, A, Puu G: Kinetics for the inhibition of acetylcholinesterase from the electric eel by some organophosphates and carbamates. J Biochem 140: 153-156, 1984

De Jong LPA, Kossen SP: Stereospecific reactivation of human brain and erythrocyte acetylcholinesterase inhibited by 1,2,2-trimethylpropyl methylphonofluoridate (soman). Biochim Biophys Acta 830: 345-348, 1985

Kovach IM: Structure and dynamics of serine hydrolase-organophosphate adducts. J Enz Inhib 2: 199-208, 1988

Ennis M, Shipley MT: Tonic activation of locus coeruleus neurons by systemic or intracoerulear microinjection of an irreversible acetylcholinesterase inhibitor: increased discharge rate and induction of C-fos. Exper Neur 118: 164-177, 1992

Zang LY, Misra HP: Acetylcholinesterase inhibition by 1-methyl-4-phenylpyridium ion, a bioactivated metabolite of MPTP. Mol Cell Biochem 126: 93-100, 1993

Zang LY, Misra HP: Inhibition of acetylcholinesterase by neurotoxicant, 1-methyl-4-phenyl-2,3-dihydropyridium ion. Arch Biochem Biophys 336: 147-150, 1996

Spinedi A, Pacini L, Luly P: A study of the mechanism by which some amphiphilic drugs affect human erythrocyte acetylcholinesterase activity. Biochem J 261: 569-573, 1989

Spinedi A, Pacini L, Limatola C, Luly P, Farias RN: Phenothiazines inhibit acetylcholinesterase by concentration-dependent-type kinetics. Biochem Pharmacol 44: 1511-1514, 1992

Zang LY, Misra HP: Superoxide radical production during the autoxidation of 1-methyl-4-phenyl-2,3-dihydropyridinium perchlorate. J Biol Chem 267: 17547-17552, 1992

Zang LY, Misra HP: EPR kinetic studies of superoxide radicals generated during the autoxidation of 1-methyl-4-phenyl-2,3,-dihydropyridinium, a bioactivated intermediate of Parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine. J Biol Chem 267: 23601-23608, 1992

Zang LY, Misra HP: Generation of reactive oxygen species during the monoamine oxidase-catalyzed oxidation of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Biol Chem 268:16504-16512, 1993

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Molecular and Cellular Biochemistry

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