IRON-CATALYZED AND MANGANESE-CATALYZED AUTOXIDATION OF DOPAMINE IN THE PRESENCE OF L-CYSTEINE - POSSIBLE INSIGHTS INTO IRON-MEDIATED AND MANGANESE-MEDIATED DOPAMINERGIC NEUROTOXICITY

Iron(II/III) and manganese(II) both catalyze the autoxidation of the n eurotransmitter dopamine (DA) in the presence of L-cysteine (CySH) in buffered aqueous solution at pH 7.4. Fe2+/Fe3+ and CySH together gener ate the hydroxyl(HO .) and cysteinyl thiyl (CyS .) radicals. DA is oxi dized by HO . to DA semiquinone radical species that either react with CyS . to give 5-S-cysteinyldopamine (5-S-CyS-DA), 8-S-CyS-DA, and 6-S -CyS-DA or disproportionate to DA-o-quinone that reacts with CySH to g ive the same cysteinyl conjugates of DA. The major product of this ini tial reaction is 5-S-CyS-DA. However, 5-S-CyS-DA can be further oxidiz ed by HO . to an o-quinone (2) that undergoes intramolecular cyclizati on to an o-quinone imine (3). The latter intermediate is the precursor of the dihydrobenzothiazine (DHBT) ihydro-5-hydroxy-2H-1,4-benzothiaz ine-3-carboxylic acid (DHBT-1) and several other cyclized products. Ho wever, cysteinyl conjugates of DA can also be oxidized by HO . in a on e-electron abstraction reaction that leads to DA thiyl radicals. React ions of these radicals with CyS . or DA semiquinone radicals lead to s ome novel DA disulfides and thioethers, respectively. The Mn(II)-catal yzed oxidation of DA generates DA-o-quinone that is scavenged by CySH to give 5-S-CyS-DA (major initial product) with lower yields of other cysteinyldopamines. Subsequent Mn(II)-catalyzed oxidation of 5-S-CyS-D A gives o-quinone 2 and thence o-quinone imine 3 that serve as the pre cursors of DHBT-1 and several other DHBTs. Organic or oxygen radicals do not play significant roles in the Mn(II)-catalyzed oxidation of DA in the presence of CySH. Recent studies have demonstrated that DHBT-1 can be accumulated by brain mitochondria and evoke irreversible inhibi tion of NADH-coenzyme Q reductase (complex I). Furthermore, iron, mang anese, and alterations in glutathione and CySH metabolism have been im plicated in the selective degeneration of nigrostriatal dopaminergic n eurons in idiopathic and chemically induced Parkinson's disease (PD). Because DHBT-1 is formed in both the iron- and manganese-catalyzed oxi dation of DA in the presence of CySH and a defect in mitochondrial com plex I respiration contributes to dopaminergic neuronal cell death in PD, the results of this investigation are discussed in terms of their possible implications to an understanding of the neuropathological pro cesses in idiopathic and chemically induced parkinsonism.