Role of Endogenous Glutathione in the Oxidation of Dopamine


Address correspondence and reprint requests to Dr. T. G. Hastings at Department of Neurology/Neuroscience, S-505 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.


Abstract: Intrastriatal injection of dopamine causes the selective degeneration of tyrosine hydroxylase-containing terminals and an increase in content of cysteinylcatechols, an index of dopamine oxidation. Both of these effects can be attenuated by coadministration of antioxidants such as glutathione. Therefore, we investigated the effects of decreased endogenous glutathione on the neurotoxic potential of dopamine. We observed that pretreatment with either l-buthionine sulfoximine, a specific inhibitor of glutathione synthesis, or diethyl maleate, which forms adducts with glutathione, caused significant decreases in endogenous glutathione levels at the time of dopamine injection. Pretreatment with l-buthionine sulfoximine potentiated the formation of protein cysteinyl-dopamine after intrastriatal injection of 1.0 µmol of dopamine. We also observed that intrastriatal injection of 1.0 µmol of dopamine decreased striatal glutathione content in all pretreatment conditions. However, injection of a low dose (0.05 µmol of dopamine) caused a decrease in striatal glutathione levels only in the l-buthionine sulfoximine-pretreated rats. Diethyl maleate pretreatment was not effective in potentiating either cysteinyl-catechol formation or glutathione loss after dopamine injection. We conclude that dopamine contributes to cellular oxidative stress and that this can be exacerbated, or at least unmasked, if glutathione synthesis is compromised.