Influence of glutathione on the oxidation chemistry of the catecholaminergic neurotransmitter dopamine

Abstract

In this study it is demonstrated that dopamine- o-quinone (DA- o-quinone), generated by the electrochemically driven oxidation of the catecholaminergic neurotransmitter dopamine (DA) at physicological pH, is rapidly scavenged by glutathione (GSH) to give, initially, 5- S-glutathionyldopamine (5- S-Glu-DA). The latter conjugate is more easily oxidized than DA to an o-quinone that reacts further with free GSH to give 2,5-bi- S-glutathionyldopamine ( 6), an even more easily oxidized compound. The proximate oxidation product of 6, o-quinone ( 7), is the precursor of 2,5,6-tri- S-glutathionyldopamine ( 8) and 4,7-bi- S-glutathionyl-5,6,dihydroxyindole ( 16). A p-quinone methide tautomer of o-quinone 7 is the precursor of glutathionyl conjugates of DA which contain a glutathionyl residue substituted in the ethylamino side-chain of the neurotransmitter. In the presence of equimolar or greater concentrations of GSH the normal oxidation pathway of DA to insoluble black indolic melanin polymer is blocked. The potential relevance of the in-vitro oxidation of DA in the presence of free GSH to an understanding of the degeneration of nigrostriatal dopaminergic neurons in idiopathic Parkinson's disease is discussed.