Dopamine mercapturate can augment dopaminergic neurodegeneration

Pathological and biochemical studies have consistently associated endogenou s catechol oxidation with dopaminergic neurodegeneration in Parkinson's dis ease (PD). Recently, it has been proposed that products of catechol oxidati on, the catechol thioethers, may contribute to dopaminergic neurodegenerati on. In other organ systems, thioether cytotoxicity is influenced profoundly by the mercapturic acid pathway. We have pursued the hypothesis that endog enous catechol thioethers produced in the mercapturic acid pathway contribu te to dopaminergic neurodegeneration. Our results showed that the extent of in vitro metal-catalyzed oxidative damage by catechol thioethers varied wi th the structures of the parent catechol and thioether adduct. Catechol mer capturates uniquely produced more oxidative damage than their parent catech ols. In dopaminergic cell cultures, dopamine induced apoptosis in a concent ration-dependent manner from 5 to 50 muM. The apoptotic effect of dopamine was greatly enhanced by subcytotoxic concentrations of the mitochondrial in hibitor, N-methyl-4-phenylpyridinium (MPP+). similarly. subcytotoxic levels of the mercapturate or homocysteine conjugate of dopamine significantly au gmented dopamine-induced apoptosis. Finally, microsomal fractions of substa ntia nigra from PD patients or age-matched controls had comparable cysteine -S-conjugate N-acetyltransferase activity. These data indicate that the mer capturate conjugate of dopamine may augment dopaminergic neurodegeneration and that the mercapturate pathway exists in human substantia nigra.