Di Monte D, Irwin I, Kupsch A, Cooper S, DeLanney L E, Langston J W
Institute for Medical Research, San Jose, CA 95128.
Eur J Pharmacol. 1989 Jul 4;166(1):23-9. doi: 10.1016/0014-2999(89)90679-1.
Diethyldithiocarbamate (DDC) was found to inhibit the uptake of both dopamine and 1-methyl-4-phenyl-pyridinium ion (MPP+, the putative toxic metabolite of the neurotoxicant MPTP) by striatal synaptosomes. Disulfiram, the corresponding disulfide of DDC, was effective at concentrations 1,000 times lower (10(-6) vs. 10(-3) M). Disulfiram, but not DDC, reacted very efficiently with synaptosomal protein thiols; both DDC- and disulfiram-induced uptake inhibition could be reversed by the thiol-reducing agent dithiothreitol. Two other thiol-reactive compounds, N-ethylmaleimide (NEM) and p-hydroxymercuribenzoate (PMB), also impaired the uptake of MPP+ by striatal synaptosomes. PMB, which does not cross membranes, was even more potent than the lipophilic NEM in blocking MPP+ uptake. These results suggest that (1) the effect of DDC may be mediated by disulfiram, (2) the uptake of MPP+ and dopamine by striatal synaptosomes is dependent on the redox state of protein thiols, and (3) these protein thiols are located at the outer surface of synaptosomal membranes.
二乙基二硫代氨基甲酸盐（DDC）被发现可抑制纹状体突触体对多巴胺和1-甲基-4-苯基吡啶离子（MPP⁺，神经毒素MPTP的假定有毒代谢物）的摄取。双硫仑，DDC的相应二硫化物，在浓度低1000倍时（10⁻⁶对10⁻³ M）仍有效。双硫仑，而非DDC，能非常有效地与突触体蛋白硫醇反应；DDC和双硫仑诱导的摄取抑制均可被硫醇还原剂二硫苏糖醇逆转。另外两种硫醇反应性化合物，N-乙基马来酰亚胺（NEM）和对羟基汞苯甲酸（PMB），也损害纹状体突触体对MPP⁺的摄取。不能穿过细胞膜的PMB在阻断MPP⁺摄取方面甚至比亲脂性的NEM更有效。这些结果表明：（1）DDC的作用可能由双硫仑介导；（2）纹状体突触体对MPP⁺和多巴胺的摄取取决于蛋白硫醇的氧化还原状态；（3）这些蛋白硫醇位于突触体膜的外表面。
