Endogenous Brain Catechol Thioethers in Dopaminergic Neurodegeneration

Abstract

Pathological and biochemical studies have consistently associated endogenous catechol oxidation with dopaminergic neurodegeneration in Parkinson’s disease (PD). Recently it has been proposed that products of catechol oxidation, the catechol thioethers, may contribute to dopaminergic neurodegeneration. In other organ systems, thioether cytotoxicity is influenced profoundly by the mercapturic acid pathway. We have pursued the hypothesis that endogenous catechol thioethers produced in the mercapturic acid pathway contribute to dopaminergic neurodegeneration. Our results showed that in vitro metal-catalyzed oxidative damage by catechol thioethers varied with the structures 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-dependent manner from 5 to 50 µM. The apoptotic effect of dopamine was greatly enhanced by subcytotoxic concentrations of he mitochondrial inhibitor, N-methyl-4-phenylpyridinium (MPP+). Similarly, subcytotoxic levels of the mercapturate or homocysteine conjugate of dopamine significantly augmented dopamineinduced apoptosis. Finally, microsomal fractions of substantia nigra from PD patients and age-matched controls had comparable cysteine-S-conjugate N-acetyltransferase activity. These data indicate that the mercapturate conjugate of dopamine may augment dopaminergic neurodegeneration and that the mercapturate pathway exists in human substantia nigra.