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  • Title: Diethyldithiocarbamate and disulfiram inhibit MPP+ and dopamine uptake by striatal synaptosomes.
    Author: Di Monte D, Irwin I, Kupsch A, Cooper S, DeLanney LE, Langston JW.
    Journal: Eur J Pharmacol; 1989 Jul 04; 166(1):23-9. PubMed ID: 2553428.
    Abstract:
    Diethyldithiocarbamate (DDC) was found to inhibit the uptake of both dopamine and 1-methyl-4-phenyl-pyridinium ion (MPP+, the putative toxic metabolite of the neurotoxicant MPTP) by striatal synaptosomes. Disulfiram, the corresponding disulfide of DDC, was effective at concentrations 1,000 times lower (10(-6) vs. 10(-3) M). Disulfiram, but not DDC, reacted very efficiently with synaptosomal protein thiols; both DDC- and disulfiram-induced uptake inhibition could be reversed by the thiol-reducing agent dithiothreitol. Two other thiol-reactive compounds, N-ethylmaleimide (NEM) and p-hydroxymercuribenzoate (PMB), also impaired the uptake of MPP+ by striatal synaptosomes. PMB, which does not cross membranes, was even more potent than the lipophilic NEM in blocking MPP+ uptake. These results suggest that (1) the effect of DDC may be mediated by disulfiram, (2) the uptake of MPP+ and dopamine by striatal synaptosomes is dependent on the redox state of protein thiols, and (3) these protein thiols are located at the outer surface of synaptosomal membranes.
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