Vaccari A, Saba P
Department of Neuroscience B. Brodie, Medical School, University of Cagliari, Italy.
Eur J Pharmacol. 1995 Mar 16;292(3-4):309-14. doi: 10.1016/0926-6917(95)90037-3.
This study defined the ability of a large sample of heterogeneous pesticides and neurotoxins to interact with the [3H]tyramine-labelled vesicular transporter of dopamine in rat striatum. Botanical (with rotenone as the most potent), and organochlorine (Kepone) insecticides, as well as fungicides (Zineb), as a whole, consistently inhibited [3H]tyramine binding, with Ki values ranging from 5 nM to 10 microM. ATP/Mg(2+)-dependent [3H]tyramine uptake to purified striatal synaptic vesicles was also inhibited by rotenone. Organophosphate and carbamate insecticides, and miscellaneous herbicides poorly antagonized [3H]tyramine binding, yielding Ki values exceeding 10 microM. Several, though not all, of the best recognized central neurotoxins tested were major binding antagonists. Their rank order of potency was 1-methyl-4-phenylpyridinium ion (MPP+) > trimethyltin > or = 6-hydroxydopamine > N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) > 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with Ki values ranging from 35 nM to 3 microM. Overall, the potent interaction of selected pesticides and chemicals with the vesicular transporter for dopamine, although, by itself, not synonymous with neurotoxicity, would argue for a likely impairment of transmitter homeostasis, or the putative formation of neurodegenerative toxin pools.
本研究确定了大量异质性农药和神经毒素与大鼠纹状体中[3H]酪胺标记的多巴胺囊泡转运体相互作用的能力。植物源杀虫剂（鱼藤酮效力最强）、有机氯杀虫剂（开蓬）以及杀菌剂（代森锌）总体上一致抑制[3H]酪胺结合，其抑制常数（Ki）值范围为5 nM至10 μM。鱼藤酮也抑制ATP/Mg(2+)依赖性的[3H]酪胺摄取至纯化的纹状体突触囊泡。有机磷和氨基甲酸酯类杀虫剂以及其他除草剂对[3H]酪胺结合的拮抗作用较弱，其Ki值超过10 μM。所测试的几种（并非全部）最知名的中枢神经毒素是主要的结合拮抗剂。它们的效力排序为1-甲基-4-苯基吡啶离子（MPP+）>三甲基锡>或 = 6-羟基多巴胺>N-(2-氯乙基)-N-乙基-2-溴苄胺（DSP-4）>1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），Ki值范围为35 nM至3 μM。总体而言，所选农药和化学物质与多巴胺囊泡转运体的强烈相互作用，虽然其本身并非神经毒性的同义词，但表明可能会破坏递质稳态，或可能形成神经退行性毒素池。
