RT Journal Article
SR Electronic
T1 Dithiocarbamate Pesticides Affect Glutamate Transport in Brain Synaptic Vesicles
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1
OP 5
VO 288
IS 1
A1 Vaccari, Andrea
A1 Saba, Pierluigi
A1 Mocci, Ignazia
A1 Ruiu, Stefania
YR 1999
UL http://jpet.aspetjournals.org/content/288/1/1.abstract
AB Dithiocarbamate compounds are widely used agricultural fungicides that display low acute toxicity in mammals and that may become neurotoxic after prolonged exposure. Mancozeb, among other dithiocarbamates tested, proved to be the most potent (Ki= 0.27 μM) at noncompetitively inhibiting the in vitro ATP-dependent uptake of [3H]glutamate in rat cortical vesicles. Furthermore, mancozeb partially (20%) inhibited the ATP-dependent uptake of [14C]methylamine, used as an index for the vesicular transmembrane proton gradient (ΔpH), and evoked its efflux from organelles previously incubated with the3H-labeled marker. Meanwhile, the vesicular uptake of36chloride− anions whose concentrations regulate the transmembrane potential gradient (ΔψSV) was not impaired. The dithiocarbamate effects on the vesicular transport of [3H]glutamate thus appeared to involve mainly the ΔpH gradient rather than the potential gradient. Dithiocarbamate metabolites, the potent neurotoxin carbon disulfide included, did not affect the uptake process, thus implying the relevance for inhibition of the persistence, if any, of parent compounds in the brain. The present novel and potent in vitro interferences of selected dithiocarbamate pesticides with the vesicular transport of glutamate, if representative of in vivo alterations, may play some role in the probably complex origin of dithiocarbamate neurotoxicity. The American Society for Pharmacology and Experimental Therapeutics