Endogenous catechol thioethers may be pro-oxidant or antioxidant.
Increased catechol thioether formation is associated with Parkinson's disease. In this study, we examined whether catechol thioethers, having a lower oxidation potential than their parent catechols, would cause greater oxidative damage than their parent catechols. We synthesized 5'-S-glutathionyl, cysteinyl, and N-acetylcysteinyl derivatives of dopamine and dopac, encompassing the known catechol thioethers of the mercapturate pathway. Cyclic voltametry studies showed that catechol thioethers had higher reduction potentials than their parent catechols. A higher reduction potential did not correlate with an increase in oxidative damage, measured by metal-catalyzed DNA strand breakage. 5'-S-Glutathionyldopamine and the cysteinyl adducts of dopamine and dopac mediated less oxidative damage than their parent catechols. In contrast, both N-acetylcysteinyl analogs were equipotent to dopamine. Oxygen consumption corresponded to DNA damage except for 5'-S-glutathionyldopamine. The glutathionyl and cysteinyl adducts of dopamine inhibited dopamine-mediated DNA damage indicating that these adducts may have antioxidant properties. 5'-S-Glutathionyldopamine potentiated H2O2-mediated damage whereas 5-S-cysteinyldopamine was inhibitory. Our results show that the ability of catechol thioethers to cause oxidative damage in vitro is not based simply upon the reduction potential but rather, reflects a complex relationship among structures of the parent catechol and thiol adduct, metal catalyst, and oxidant.
Picklo
M J
MJ
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. matthew.picklo@mcmail.vanderbilt.edu
Amarnath
V
V
Graham
D G
DG
Montine
T J
TJ
D000975:Antioxidants / Q000378:metabolism*; D002396:Catechols / Q000378:metabolism*; D004249:DNA Damage; D004269:DNA, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D016877:Oxidants / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism*
D000975:Antioxidants; D002396:Catechols; D004269:DNA, Bacterial; D016877:Oxidants; D017382:Reactive Oxygen Species; D013440:Sulfides