Increased synaptosomal dopamine content and brain concentration of paraquat produced by selective dithiocarbamates.
Exposure to pesticides may be a risk factor for Parkinson's disease based on epidemiologic data in humans, animal models and in vitro studies. Different dithiocarbamate pesticides potentiate the toxicity of both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and paraquat in mouse models of Parkinsonism by an unknown mechanism. This study examined the effects of commercially used dithiocarbamates on [3H]dopamine transport in striatal synaptosomal vesicles and on the concentration of [14C]paraquat in vivo in mice. Different ethylenebis-dithiocarbamates and diethyl-dithiocarbamate increased dopamine accumulation in synaptosomes, whereas dimethyl-dithiocarbamate and methyl-dithiocarbamate did not. Increased dopamine accumulation in synaptosomes was dose dependent and was related to the carbon backbone of these molecules. The dithiocarbamates that increased accumulation of dopamine did not alter the influx of dopamine, but rather delayed the efflux out of synaptosomes. These same dithiocarbamates also increased the tissue content of [14C]paraquat in vivo by a mechanism that appeared to be distinct from the dopamine transporter. There was a consistent relationship between the dithiocarbamates that increased synaptosomal accumulation of dopamine and tissue content of paraquat, with those previously demonstrated to enhance paraquat toxicity in vivo. These results suggest that selective dithiocarbamates may alter the kinetics of different endogenous and exogenous compounds to enhance their neurotoxicity.
Barlow
Brian K
BK
Department of Pathology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Thiruchelvam
Mona J
MJ
Bennice
Lisa
L
Cory-Slechta
Deborah A
DA
Ballatori
Nazzareno
N
Richfield
Eric K
EK
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D005028:Ethylenebis(dithiocarbamates) / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D010269:Paraquat / Q000032:analysis* / Q000493:pharmacokinetics; D010575:Pesticides / Q000493:pharmacokinetics / Q000494:pharmacology; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology*
D050483:Dopamine Plasma Membrane Transport Proteins; D005028:Ethylenebis(dithiocarbamates); D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds; D010575:Pesticides; D013859:Thiocarbamates; C471036:manganese ethylenebis(dithiocarbamate); D003042:Cocaine; D010269:Paraquat; D004298:Dopamine