Abstract
Pathological and biochemical studies have consistently associated endogenous catechol oxidation with dopaminergic neurodegeneration in Parkinson’s disease (PD). Recently it has been proposed that products of catechol oxidation, the catechol thioethers, may contribute to dopaminergic neurodegeneration. In other organ systems, thioether cytotoxicity is influenced profoundly by the mercapturic acid pathway. We have pursued the hypothesis that endogenous catechol thioethers produced in the mercapturic acid pathway contribute to dopaminergic neurodegeneration. Our results showed that in vitro metal-catalyzed oxidative damage by catechol thioethers varied with the structures of the parent catechol and thioether adduct. Catechol mercapturates were unique in producing more oxidative damage than their parent catechols. In dopaminergic cell cultures, dopamine induced apoptosis in a concentration-dependent manner from 5 to 50 µM. The apoptotic effect of dopamine was greatly enhanced by subcytotoxic concentrations of he mitochondrial inhibitor, N-methyl-4-phenylpyridinium (MPP+). Similarly, subcytotoxic levels of the mercapturate or homocysteine conjugate of dopamine significantly augmented dopamineinduced apoptosis. Finally, microsomal fractions of substantia nigra from PD patients and age-matched controls had comparable cysteine-S-conjugate N-acetyltransferase activity. These data indicate that the mercapturate conjugate of dopamine may augment dopaminergic neurodegeneration and that the mercapturate pathway exists in human substantia nigra.
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References
Aigner, A., Jager, M., Pasternack, R., Weber, P., Wienke, D., and Wolf, S., 1996, Purification and characterization of cysteine-S-conjugate N-acetyltransferase from pig kidney, Biochem. J. 317: 213.
Alam, Z. I., Jenner, A., Daniel, S. E., Lees, A. J., Cairns, N., Marsden, C. D., Jenner, P., and Halliwell, B., 1997, Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanosine levels in the substantia nigra, J. Neurochem. 69:1196.
Calne, D. B., 1993, Treatment of Parkinson’s disease, New Engl. J. Med. 329: 1021.
Cohen, G. and Werner, P., 1994, Free radicals, oxidative stress, and neurodegeneration, in:Neurodegenerative Diseases, D. B. Calne, ed., Philadelphia, PA: W B Saunders, pp. 139.
Corral-Debrinski, ML, Horton, T., Lott, M. T., Shoffner, J. M., Beal, M. F., and Wallace, D. C., 1992, Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age, Nat. Genetics 2: 324.
Coyle, J. T. and Puttfarcken, P., 1993, Oxidative stress, glutamate, and neurodegenerative disorders, Science 262: 689.
Damier, P., Hirsch, E. C., Zhang, P., Agid, Y., and Javoy-Agid, F., 1993, Glutathione peroxidase, glial cells and Parkinson’s disease, Neuroscience 52: 1.
Dexter, D. T., Carter, C. J., Wells, F. R., Javoy-Agid, F., Agid, Y., Lees, A., Jenner, P., and Marsden, C.D., 1989, Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease, J. Neurochem. 52: 381.
Fahn, S., 1991, An open trial of high-dose antioxidants in early Parkinson’s disease, Am. J. Clin. Nutr. 53: 380.
Fornstedt, B., Pileblad, E., and Carlsson, A., 1990, In vivo autoxidation of dopamine in guinea pig striatum increases with age, J. Neurochem. 55: 655.
Fornstedt, B., Rosengren, E., and Carlsson, A., 1986, Occurrence and distribution of 5-Scysteinyl derivatives of dopamine, dopa, and dopac in the brains of eight mammalian species, Neuropharmacology 25: 451.
Fornstedt, B., Rosengren, E., and Carlsson, A., 1989, The apparent autoxidation rate of catechols in dopamine-rich regions of human brains increases with degree of depigmentation of substantia nigra, J. Neural. Transm. 1: 279.
Globus, M. Y. T., Ginsberg, M. D., Harik, S. I., Busto, R., and Dietrich, W. D., 1987, Role of dopamine in ischemic striatal injury, Neurology 37: 1712.
Graham, D. G., 1978, Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones, Mol. Pharmacol. 14: 633.
Graham, D. G., Tiffany, S. M., Bell Jr, W. R., and Gutknecht, W. F., 1978, Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro, Mol. Pharmacol. 14:644.
Green, D. R. and Reed, J. C., 1998, Mitochondria and apoptosis, Science 281: 1309.
Halliwell, B., 1992, Reactive oxygen species and the central nervous system, J. Neurochem. 59:1609.
Hastings, T. G., Lewis, D. A., and Zigmond, M. J., 1996, Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections, Proc. Natl. Acad. Sci. 93: 1956.
Hirsch, E. C., 1992, Why are nigral catecholaminergic neurons more vulnerable than other cells in Parkinson’s disease?, Ann. Neurol. 32: S88.
Hirsch, E., Graybiel, A. M., and Agid, Y. A., 1988, Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease, Nature 334: 345.
Jenner, P., Dexter, D. T., Sian, J., Schapira, A. H., and Marsden, C. D., 1992, Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson’s Disease Research Group, Ann. Neurol. 32: S82.
Jenner, P. J. and Olanow, C. W., 1998, Understanding cell death in Parkinson’s disease, Ann. Neurol. 44: S72.
Koller, W. C, 1998, Neuroprotection for Parkinson’s disease, Ann. Neurol. 44: S155.
Kravtsov, V. D. and Fabian, I., 1996, Automated monitoring of apoptosis in suspension cell cultures, Lab. Invest. 74: 557.
Kravtsov, V. D., Greer, J. P., Whitlock, J. A., and Koury, M. J., 1998, Use of the microculture kinetic assay of apoptosis to determine chemosensitivities to leukemias, Blood 92: 968.
Lang, A. E. and Lozano, A. M., 1998, Parkinson’s disease, New Engl. J. Med. 339: 1044-1053 and 1130.
Le, W.D., Colom, L.V., Xie, W.J., Smith, R.G., Alexianu, M., and Appel, S.H., 1995, Cell death induced by beta-amyloid 1-40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis, Brain Res. 686: 49.
Li, H., Shen, X. M., and Dryhurst, G., 1998, Brain mitochondria catalyze the oxidation of 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1) to intermediates that irreversibly inhibit complex I and scavenge glutathione: potential relevance to the pathogenesis of Parkinson’s disease, J. Neurochem. 71: 2049.
Li, H. and Dryhurst, G., 1997, Irreversible inhibition of mitochondrial complex I by 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1): a putative nigral endotoxin of relevance to Parkinson’s disease, J. Neurochem. 69: 1530.
Mann, D. M. A. and Yates, P. O., 1982, Pathogenesis of Parkinson’s disease, Arch. Neurol. 39:545.
Mann, D. M. A. and Yates, P. O., 1983, Possible role of neuromelanin in the pathogenesis of Parkinson’s disease, Mech. Aging and Develop. 21: 193.
Miller, R. T., Lau, S. S., and Monks, T. J., 1995, Metabolism of 5-(glutathion-S-y1)-α-methyl- dopamine following intracerebroventricular administration to male Sprague-Dawley rats, Chem. Res. Toxicol. 8: 634.
Monks, T. J., Hanzlik, R. P., Cohen, G. M., Ross, D., and Graham, D. G., 1992, Quinone chemistry and toxicology, Toxicol. Appl. Pharmacol. 112: 2.
Monks, T. J. and Lau, S. S., 1992, Toxicology of quinone-thioethers, Critical Rev. Toxicol. 22:243. Montine, T. J., Farris, D. B., and Graham, D. G., 1995, Covalent crosslinking of neurofilament proteins by oxidized catechols as a potential mechanism of Lewy body formation, J.Neuropathol. Exp. Neurol. 54: 311.
Montine, T. J., Picklo, M. J., Amarnath, V., Whetsell, W. O., and Graham, D. G., 1997, Neurotoxicity of endogenous cysteinylcatechols, Exp. Neurol. 148: 26.
Montine, T. J., Underhill, T. M., Linney, E., and Graham, D. G., 1994, Fibroblasts that express aromatic amino acid decarboxylase have increased sensitivity to the synergistic cytotoxicity of L-dopa and manganese, Toxicol. Appl. Pharmacol. 128: 116.
Olanow, C. W., 1990, Oxidative reactions in Parkinson’s disease, Neurology 40: S32.
Parkinson’s Disease Study Group, 1989, Effect of depreny1 on the progression of disability in early Parkinson’s disease, N. Engl. J. Med. 321: 1364.
Picklo, M. J., Amaranth, V., Graham, D. G., and Montine, T. J., 1999, Endogenous catechol thioethers may be pro-oxidant or anti-oxidant, Free Radicals Biol. Med. 27: 271.
Przedborski, S., Jackson-Lewis, V., Muthane, U., Jiang, H., Ferreira, M., Naini, A. B., and Fahn, S., 1993, Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity, Neurology 34: 715.
Shen, X. M., Xia, B., Wrona, M. Z., and Dryhurst, G., 1996a, Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine:possible metabolites of relevance to Parkinson’s disease, Chem. Res. Toxicol. 9: 1117.
Shen, X. M. and Dryhurst, G., 1996b, Further insights into the influence of L-cysteine on the oxidation chemistry of dopamine: reaction pathways of potential relevance to Parkinson’s disease, Chem. Res. Toxicol. 9: 751.
Sian, J., Dexter, D. T., and Lees, A. J., 1994, Glutathione related enzymes in brain in Parkinson’s disease, Ann. Neurol. 36: 356.
Spencer, J. P. E., Jenner, P., Daniel, S. E., Lees, A. J., Marsden, D. C., and Halliwell, B., 1998, Conjugates of catecholamines with cysteine and GSH in Parkinson’s disease: possible mechanisms of formation involving reactive oxygen species, J. Neurochem. 71: 2112.
Wang, W. and Ballatori, N., 1998, Endogenous glutathione conjugates: occurrence and biological functions, Pharmacol. Rev. 50: 335.
Zhang, J., Price, J. O., Graham, D. G., and Montine, T. J., 1998, Secondary excitotoxicity contributes to dopamine-induced apoptosis of dopaminergic neuronal cultures, Biochem. Biophys. Res. Comm. 248: 812.
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Montine, T.J., Amarnath, V., Picklo, M.J., Sidell, K.R., Zhang, J., Graham, D.G. (2000). Endogenous Brain Catechol Thioethers in Dopaminergic Neurodegeneration. In: Storch, A., Collins, M.A. (eds) Neurotoxic Factors in Parkinson’s Disease and Related Disorders. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1269-1_17
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DOI: https://doi.org/10.1007/978-1-4615-1269-1_17
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