Enhancement of dopaminergic neurotoxicity by the mercapturate of dopamine:Relevance to Parkinson's disease

The mechanisms that underlie dopaminergic neurodegeneration in Parkinson's disease (PD) are not known but have been proposed to involve oxidation of d opamine and related catechols. In other organ systems, cytotoxicity from ca techol oxidation is profoundly influenced by mercapturate metabolism. Here we have tested the hypothesis that catechol thioethers produced in the merc apturic acid pathway may act as dopaminergic neurotoxins. A rat mesencephal ic/neuroblastoma hybrid (MES) cell line was exposed to dopamine, 3,4-dihydr oxyphenylacetic acid (DOPAC), or eight different catechol thioethers for up to 24 h, and the extent of apoptosis was quantified by a microculture kine tic assay. Apoptosis also was confirmed morphologically with Giemsa-stained cultures and by demonstration of internucleosomal DNA fragmentation. The r esults showed that dopamine at 5-50 mu M produced concentration-dependent i ncreases in the percentage of apoptotic MES cells. At 25 and 50 mu M dopami ne, the maximal proportions of apoptotic cells were detected at similar to 19 (20.7 +/- 2.0%) and 14 h (30.3 +/-. 3.5%), respectively. None of the cat echol thioethers (up to 5 mu M) alone induced significant apoptosis in MES cells. However, when MES cells were incubated with dopamine (25 mu M) and c atechol thioethers (5 mu M) to mimic pathological conditions, 5-S-N-acetylc ysteinyldopamine, 5-S-homocysteinyldopamine, and 5-S-homocysteinyl-DOPAC si gnificantly increased the percentage of apoptotic cells compared with dopam ine alone. These results suggest that mercapturate metabolism of endogenous catechols may yield products that facilitate dopaminergic neurodegeneratio n.