Bertram B, Frei E, Scherf H R, Schuhmacher J, Tacchi A M, Wiessler M
J Cancer Res Clin Oncol. 1985;109(1):9-15. doi: 10.1007/BF01884248.
The influence of a prolonged treatment with disulfiram (DSF) and D(-)penicillamine (PA) on biological and biochemical effects induced by nitrosodiethylamine (NDEA) was studied in rats. The combination of NDEA and DSF led to a massive and early development of esophageal tumors, which were fatal to the animals. No liver tumors were observed in this group, whereas PA in combination with NDEA led to an increased development of liver tumors compared with NDEA alone. In the last two groups, only incidental tumors of the esophagus were observed. Nasal cavity tumors also appeared earlier in the animals treated with DSF and NDEA than in animals treated with NDEA alone or with NDEA plus PA. At a biochemical level, DSF led to a significant inhibition of hepatic anilinehydroxylase and nitroso-dimethylaminedemethylase in contrast to PA, which had no influence on these enzymes. The reduced activities of these drug-metabolizing enzymes did not appear to be related to gross cytochrome P450 content. Highly significant increases in glutathione content and glutathione-S-transferase activity (GSH/GST) were induced by DSF but not by PA. Because N-nitrosodiethylamine requires enzymatic activation to form the ultimate carcinogen, it is suggested that the observed inhibition of nitrosamine-transforming enzymes in the liver during DSF treatment leads to an increased amount of intact nitrosamines in other organs, e.g., in the esophagus, where it could be transformed to the ultimate carcinogen. DSF treatment alone or in combination with NDEA leads to an accumulation of trace elements in the liver, whereas PA eliminated copper and cobalt. The possible influence of these elements on tumor development is discussed in part II of this study.
在大鼠中研究了用双硫仑（DSF）和D（-）青霉胺（PA）进行长期治疗对亚硝基二乙胺（NDEA）诱导的生物学和生化效应的影响。NDEA与DSF的组合导致食管肿瘤大量早期发展，这对动物是致命的。该组未观察到肝肿瘤，而PA与NDEA联合使用导致肝肿瘤的发生比单独使用NDEA增加。在最后两组中，仅观察到偶发的食管肿瘤。鼻腔肿瘤在接受DSF和NDEA治疗的动物中也比单独接受NDEA或NDEA加PA治疗的动物出现得更早。在生化水平上，与PA不同，DSF导致肝苯胺羟化酶和亚硝基二甲基胺脱甲基酶的显著抑制，而PA对这些酶没有影响。这些药物代谢酶活性的降低似乎与细胞色素P450的总含量无关。DSF诱导谷胱甘肽含量和谷胱甘肽-S-转移酶活性（GSH/GST）显著增加，而PA则没有。由于N-亚硝基二乙胺需要酶促活化才能形成最终致癌物，因此表明在DSF治疗期间观察到的肝脏中亚硝胺转化酶的抑制导致其他器官（例如食管）中完整亚硝胺的量增加，在那里它可以转化为最终致癌物。单独使用DSF或与NDEA联合使用会导致肝脏中微量元素的积累，而PA则会消除铜和钴。这些元素对肿瘤发展的可能影响将在本研究的第二部分中讨论。
