Endogenous catechol thioethers may be pro-oxidant or antioxidant

Increased catechol thioether formation is associated with Parkinson's disea se. In this study, we examined whether catechol thioethers, having a lower oxidation potential than their parent catechols, would cause greater oxidat ive damage than their parent catechols. We synthesized 5'-S-glutathionyl, c ysteinyl, and N-acetylcysteinyl derivatives of dopamine and dopac, encompas sing the known catechol thioethers of the mercapturate pathway. Cyclic volt ametry studies showed that catechol thioethers had higher reduction potenti als than their parent catechols. A higher reduction potential did not corre late with an increase in oxidative damage, measured by metal-catalyzed DNA strand breakage. 5'-S-Glutathionyldopamine and the cysteinyl adducts of dop amine and dopac mediated less oxidative damage than their parent catechols. In contrast, both N-acetylcysteinyl analogs were equipotent to dopamine. O xygen consumption corresponded to DNA damage except for 5'-S-glutathionyldo pamine. The glutathionyl and cysteinyl adducts of dopamine inhibited dopami ne-mediated DNA damage indicating that these adducts may have antioxidant p roperties. 5'-S-Glutathionyldopamine potentiated H2O2-mediated damage where as 5-S-cysteinyldopamine was inhibitory. Our results show that the ability of catechol thioethers to cause oxidative damage in vitro is not based simp ly upon the reduction potential but rather, reflects a complex relationship among structures of the parent catechol and thiol adduct, metal catalyst, and oxidant. (C) 1999 Elsevier Science Inc.