title: Dopamine mercapturate can augment 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 the extent of in vitro metal-catalyzed oxidative damage by catechol thioethers varied with the structures of the parent catechol and thioether adduct. Catechol mercapturates uniquely produced more oxidative damage than their parent catechols. In dopaminergic cell cultures, dopamine induced apoptosis in a concentration-dependent manner from 5 to 50 microM. The apoptotic effect of dopamine was greatly enhanced by subcytotoxic concentrations of the mitochondrial inhibitor, N-methyl-4-phenylpyridinium (MPP+). Similarly, subcytotoxic levels of the mercapturate or homocysteine conjugate of dopamine significantly augmented dopamine-induced apoptosis. Finally, microsomal fractions of substantia nigra from PD patients or 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.
authors.affiliation: Department of Pathology, Center for Molecular Neurosciences, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Montine
authors.forename: V
authors.initials: V
authors.lastname: Amarnath
authors.forename: M J
authors.initials: MJ
authors.lastname: Picklo
authors.forename: K R
authors.initials: KR
authors.lastname: Sidell
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: D G
authors.initials: DG
authors.lastname: Graham
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D003545:Cysteine / Q000737:chemistry; D004298:Dopamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009410:Nerve Degeneration; D011954:Receptors, Dopamine / Q000378:metabolism; D013574:Synaptosomes / Q000201:enzymology
chemical_list: D002396:Catechols; D011954:Receptors, Dopamine; D001191:Arylamine N-Acetyltransferase; D003545:Cysteine; D004298:Dopamine; D000111:Acetylcysteine