Further insights into the influence of L-cysteine on the oxidation chemistry of dopamine: reaction pathways of potential relevance to Parkinson's disease.
The initial step in the genesis of neuromelanin, a black polymeric pigment normally found in the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN), is the autoxidation of dopamine (DA) to DA-o-quinone (1). In this investigation, it is demonstrated that in the presence of L-cysteine (CySH) o-quinone 1 is scavenged to give 5-S-cysteinyldopamine (5-S-Cys-DA, major product) and 2-S-cysteinyldopamine (2-S-CyS-DA, minor product). These cysteinyl conjugates are more easily oxidized than DA. The relative yields of the resulting products are dependent on the concentration of free CySH. These products include 2,5-bi-S-cysteinyldopamine (2,5-bi-S-CyS-DA) and 2,5,6-tri-S-cysteinyldopamine (2,5,6-tri-S-CyS-DA), 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5), and a number of cysteinyl conjugates of these dihydrobenzothiazines (DHBTs). 2,5-Bi-S-CyS-DA, DHBT-1, the 6-S-cysteinyl conjugate of DHBT-1, DHBT-5, and the 6-S-cysteinyl conjugate of DHBT-5 were lethal when administered into the brains of laboratory mice and evoke a very characteristic hyperactivity syndrome and episodes of severe tremor. These and related results provide support for the hypothesis that the massive, irreversible loss of glutathione (GSH), increased 5-S-CyS-DA/DA concentration ratio, and depigmentation of dopaminergic neurons in the SN that all occur in Parkinson's disease (PD) might be caused by the gamma-glutamyl transpeptidase-mediated translocation of CySH (and/or GSH) into these cells. Furthermore, the resulting cysteinyldopamines and DHBTs might include endotoxic metabolites responsible for the selective degeneration of nigrostriatal dopaminergic neurons and PD.
Shen
X M
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
Dryhurst
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D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D001921:Brain / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry*; D003548:Cysteinyldopa / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D004298:Dopamine / Q000032:analysis / Q000737:chemistry*; D004563:Electrochemistry; D004566:Electrodes; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000209:etiology*; D013056:Spectrophotometry, Ultraviolet; D013843:Thiazines / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity
D000970:Antineoplastic Agents; D013843:Thiazines; D003548:Cysteinyldopa; C097624:2,3-dihydro-1,4-benzothiazine; D003545:Cysteine; D004298:Dopamine