Endogenous brain catechol thioethers in 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 oxidatio n, the catechol thioethers, may contribute to dopaminergic neurodegeneratio n. In other organ systems, thioether cytotoxicity is influenced profoundly by the mercapturic acid pathway. We have pursued the hypothesis that endoge nous catechol thioethers produced in the mercapturic acid pathway contribut e to dopaminergic neurodegeneration. Our results showed that in vitro metal -catalyzed oxidative damage by catechol thioethers varied with the structur es of the parent catechol and thioether adduct. Catechol mercapturates were unique in producing more oxidative damage than their parent catechols. In dopaminergic cell cultures, dopamine induced apoptosis in a concentration-d ependent manner from 5 to 50 muM The apoptotic effect of dopamine was great ly enhanced by subcytotoxic concentrations of the mitochondrial inhibitor, N-methyl-4-phenylpyridinium (MPP+). Similarly, subcytotoxic levels of the m ercapturate or homocysteine conjugate of dopamine significantly augmented d opamine-induced apoptosis. Finally, microsomal fractions of substantia nigr a from PD patients and age-matched controls had comparable cysteine-S-conju gate N-acetyltransferase activity. These data indicate that the mercapturat e conjugate of dopamine may augment dopaminergic neurodegeneration and that the mercapturate pathway exists in human substantia nigra.