Cysteine and mercapturate conjugates of oxidized dopamine are in human striatum but only the cysteine conjugate impedes dopamine trafficking in vitroand in vivo

Recent results have suggested that some products of mercapturic acid pathwa y (MAP) metabolism of oxidized dopamine (DA) may contribute to mesostriatal dopaminergic neurodegeneration, and that at least one product, 5-S-cystein yldopamine (Cys-DA), is elevated in patients with advanced Parkinson's dise ase (PD) who have been treated with L-DOPA. Here we investigated MAP enzyme s and products in the midbrain and striatum of control individuals and pati ents with dementia with Lewy bodies (DLB) who had less severe dopaminergic degeneration than PD patients and who were not treated with L-DOPA. We also determined the biological activity of MAP metabolites of oxidized DA using primary rat mesencephalic cultures, rat cerebral synaptosomes, and rat str iatum in vivo microdialysis. Our results showed that the human mesostriatal dopaminergic pathway generates Cys-DA but has limited enzymatic capacity f or mercapturate formation, that striatal levels of MAP products of oxidized DA are not elevated in DLB patients compared with controls, and that Cys-D A interferes with trafficking of DA in vitro and in vivo. These results ind icate that while Cys-DA is not increased in striatum of patients with mild dopaminergic neurodegeneration, it may interfere with uptake of DA in patie nts with advanced PD.