Abstract
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.
Footnotes
-
Send reprint requests to: Prof. Andrea Vaccari, Department of Neuroscience, Via Porcell 4, 09124 Cagliari. E-mail address:avaccari{at}unica.it
-
↵1 This work was supported by grants from the Regione Autonoma della Sardegna (Assessorato Difesa Ambiente, Contract 3680, 1993), and the Italian Ministry of Scientific and Technological Research (1995–1997) to A.V.
- Abbreviations:
- DDTC
- diethyldithiocarbamic acid
- Δψsv
- potential gradient
- ΔpH
- proton gradient
- Cl
- chloride
- Received March 12, 1998.
- Accepted July 21, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|