Abstract
Parkinson’s Disease (PD) is characterized by the chronic and progressive loss of dopaminergic neurons of the nigrostriatal pathway. An important theory suggests that the dopamine neurotransmitter can itself play a role in the degeneration.1–7 One hypothesis is that dopamine (DA), which is synthesized from the essential amino acid tyrosine, can be converted to a reactive quinone metabolite (Figure 1). This oxidation of the catecholamine can either occur spontaneously or be accelerated by the enzyme tyrosinase. The attractive aspect of this hypothesis is that tyrosinase is a known component of the DA neurons which are at risk in PD. The dopamine quinone product is destructive to macromolecules for two reasons. First, it is a highly reactive molecule which is capable of covalently modifying nucleophiles such as sulfhydryls and amino groups. In fact, dopamine quinone is known to covalently modify both DNA and proteins.3,6–8 Second, through a series of oxidation reactions, dopamine quinone can contribute to the production of hydrogen peroxide, Superoxide radical, and the hydroxyl radical. These very reactive chemical entities can in turn generate extensive macromolecular damage. In the present experiments, we investigated the role of tyrosinase in DA-mediated DNA damage. The central hypothesis is that tyrosinase catalyzes the formation of dopamine quinone and therefore enhances the covalent modification of DNA by DA.
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References
D.G. Graham, Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones, Mol. Pharmacol. 14:633–643 (1978).
D.G. Graham, S.M. Tiffany, W.R. Bell, Jr., and W.F. Gutknecht, 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. 14:644–653 (1978).
R.P. Mason, Free radical metabolites of foreign compounds and their toxocological significance, in: “Reviews in Biochemical Toxicology,” E. Hodson, J.R. Bend, and R.M. Philpot, ed., pp. 151-200, (1979).
C.J. Schmidt, J.K. Ritter, P.K. Sonsalla, G.R. Hanson, and J.W. Gibb, Role of dopamine in the neurotoxic effects of methamphetamine, J. Pharmacol Exp. Ther. 233:539–544 (1985).
P.P. Michel, and F. Hefti, Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture, J. Neurosci. Res. 26:428–435 (1990).
G. Lévay, and W.J. Bodell, Detection of dopamine-DNA adducts: Potential role in Parkinson’s Disease, Carcinogenesis 14:1241–1245 (1993).
T.G. Hastings, and M.J. Zigmond, Identification of catechol-protein conjugates in neostriatal slices incubated with [3H]dopamine: Impact of ascorbic acid and glutathione, J. Neuropathol. 63:1126–1132 (1994).
P. Moldéus, M. Nordenskjöld, G. Bolcsfoldi, A. Eiche, U. Haglund, and B. Lambert, Genetic toxicity of dopamine, Mut. Res. 124:9–24 (1983).
M. Miranda, D. Botti, A. Bonfigli, T. Ventura, and A. Arcadi, Tyrosinase-like activity in normal human substantia nigra, Gen. Pharmacol. 15:541–544 (1984).
M.M. Wick, and G. Fitzgerald, Inhibition of reverse transcriptase by tyrosinase generated quinones related to levodopa and dopamine, Chem.-Biol. Interact. 38:99–107 (1981).
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© 1996 Springer Science+Business Media New York
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Stokes, A.H., Brown, B.G., Lee, C.K., Doolittle, D.J., Vrana, K.E. (1996). Dopamine Covalently Modifies DNA in a Tyrosinase-Enhanced Manner. In: Fiskum, G. (eds) Neurodegenerative Diseases. GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0209-2_36
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DOI: https://doi.org/10.1007/978-1-4899-0209-2_36
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