Increased synaptosomal dopamine content and brain concentration of paraquat produced by selective dithiocarbamates
Increased synaptosomal dopamine content and brain concentration of paraquat produced by selective dithiocarbamates
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DOI：
10.1046/j.1471-4159.2003.01773.x
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发表时间：
2003-05-01
影响因子：
4.7
通讯作者：
Richfield, EK
中科院分区：
文献类型：
--
作者：
Barlow, BK;Thiruchelvam, MJ;Richfield, EK
根据人类、动物模型和体外研究的流行病学数据，接触农药可能是帕金森病的一个危险因素。不同的二硫氨基甲酸酯农药以未知的机制增强了1-甲基-4-苯基-1,2,3,6-四氢吡啶和百草枯对帕金森小鼠模型的毒性。本研究检测了商业使用的二硫代氨基甲酸酯对纹状体突触体囊泡中[(3)H]多巴胺转运和小鼠体内[(14)C]百草枯浓度的影响。不同的乙烯-二硫代氨基甲酸酯和二乙基-二硫代氨基甲酸酯增加了突触体中多巴胺的积累，而二甲基-二硫代氨基甲酸酯和甲基-二硫代氨基甲酸酯则没有。突触体中多巴胺积累的增加是剂量依赖性的，与这些分子的碳主链有关。增加多巴胺积累的二硫代氨基甲酸酯并没有改变多巴胺的流入，而是延迟了突触体的流出。这些二硫代氨基甲酸酯也通过一种似乎与多巴胺转运体不同的机制，在体内增加了[(14)C]百草枯的组织含量。二硫代氨基甲酸酯增加突触体多巴胺积累和组织中百草枯含量之间存在一致的关系，这些物质先前被证明可以增强体内百草枯的毒性。这些结果表明，选择性二硫代氨基甲酸酯可能改变不同内源性和外源性化合物的动力学，以增强其神经毒性。
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 [(3) H]dopamine transport in striatal synaptosomal vesicles and on the concentration of [(14) C]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 [(14) C]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.