Tonkin E G, Erve J C, Valentine W M
Department of Pathology, Vanderbilt University, Nashville, Tennessee 37232-2561, USA.
J Neuropathol Exp Neurol. 2000 Sep;59(9):786-97. doi: 10.1093/jnen/59.9.786.
Disulfiram is a dithiocarbamate drug used for alcohol aversion therapy that produces a distal sensorimotor peripheral neuropathy in certain individuals. Because carbon disulfide, a disulfiram metabolite, produces a peripheral neuropathy clinically similar to disulfiram, it has been postulated that disulfiram neuropathy results from CS2 release in vivo. The current study evaluated the morphological changes produced by disulfiram and the contribution of CS2-mediated protein cross-linking to disulfiram-induced neuropathy. Male Sprague-Dawley rats were administered 1% w/w disulfiram in their feed for 2, 4, 5, or 7 wk, and erythrocyte spectrin, hemoglobin, and neurofilament preparations were isolated and the extent of cross-linking assessed by SDS-PAGE, RP-HPLC, and Western blotting, respectively. Spinal cord and peripheral nerve sections were obtained from separate treated animals and assessed by light and electron microscopy. Significant protein cross-linking was only detected in neurofilament preparations obtained after 7 wk of exposure. Morphological changes were observed after 4 wk exposure and consisted of vacuoles within the Schwann cell cytoplasm and segmental demyelination. No neurofilamentous axonal swellings were detected and no significant changes were observed in the CNS. Because disulfiram neuropathy lacks both the morphological changes and intermolecular cross-linking characteristic of CS2, we conclude that disulfiram neuropathy is not mediated by the axonal toxicant CS2; instead, disulfiram appears to be a primary Schwann cell toxicant. Recognition of a diethylcarbamoyl adduct on globin and axonal proteins presents a novel putative neurotoxic mechanism for disulfiram.
双硫仑是一种用于戒酒疗法的二硫代氨基甲酸盐药物，在某些个体中会导致远端感觉运动性周围神经病变。由于双硫仑的代谢产物二硫化碳会产生与双硫仑临床相似的周围神经病变，因此推测双硫仑神经病变是由体内二硫化碳的释放引起的。本研究评估了双硫仑产生的形态学变化以及二硫化碳介导的蛋白质交联对双硫仑诱导的神经病变的作用。给雄性Sprague-Dawley大鼠在饲料中喂食1% w/w的双硫仑，持续2、4、5或7周，分离红细胞血影蛋白、血红蛋白和神经丝制剂，并分别通过SDS-PAGE、RP-HPLC和蛋白质印迹法评估交联程度。从单独处理的动物中获取脊髓和周围神经切片，通过光镜和电镜进行评估。仅在暴露7周后获得的神经丝制剂中检测到显著的蛋白质交联。暴露4周后观察到形态学变化，包括施万细胞胞质内的空泡和节段性脱髓鞘。未检测到神经丝性轴突肿胀，中枢神经系统也未观察到显著变化。由于双硫仑神经病变缺乏二硫化碳的形态学变化和分子间交联特征，我们得出结论，双硫仑神经病变不是由轴突毒物二硫化碳介导的；相反，双硫仑似乎是一种原发性施万细胞毒物。对球蛋白和轴突蛋白上二乙基氨基甲酰加合物的识别为双硫仑提出了一种新的推定神经毒性机制。
