Vinyl carbamate as a promutagen and a more carcinogenic analog of ethyl carbamate.
Vinyl carbamate as a promutagen and a more carcinogenic analog of ethyl carbamate.
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发表时间：
1978-11
期刊：
影响因子：
11.2
通讯作者：
G. Dahl;J. Miller;E. Miller
中科院分区：
文献类型：
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作者：
G. Dahl;J. Miller;E. Miller
对于引发小鼠皮肤肿瘤和诱导肺腺瘤，氨基甲酸乙烯酯的活性比氨基甲酸乙酯高得多（10至50倍）。在存在还原型烟酰胺腺嘌呤二核苷酸磷酸盐强化大鼠或小鼠肝脏线粒体上清液组分的情况下，氨基甲酸乙烯酯对鼠伤寒沙门氏菌TA 1535和TA 100也具有致突变性。细胞色素P-450抑制剂强烈抑制这种致突变活性。在不添加肝脏制剂的情况下，未观察到氨基甲酸乙烯酯的致突变活性，或在存在或不存在肝脏组分的情况下，未观察到氨基甲酸乙酯的致突变活性。采用敏感方法进行的广泛试验未能在小鼠体内检测到氨基甲酸乙烯酯作为氨基甲酸乙酯的代谢物。然而，对成年小鼠给予[乙基-1-14 C; 1，2 - 3 H]氨基甲酸乙酯后，肝脏DNA-、rRNA-和蛋白质-加合物的3 H/14 C比值彼此相似，且远低于给予氨基甲酸乙酯的比值。这些数据与大分子加合物中存在去饱和和/或氧化乙基一致。与氨基甲酸乙酯相比，氨基甲酸乙烯酯的致癌活性在质量上相似，但更强，这表明这两种氨基甲酸酯的代谢途径可能会在形成类似或相同的亲电反应物时会聚，这些亲电反应物在体内共价结合到大分子上并引发致癌作用。
Vinyl carbamate was much more active (10 to 50 times) than ethyl carbamate for the initiation of skin tumors and for the induction of lung adenomas in mice. Vinyl carbamate was also mutagenic to Salmonella typhimurium TA 1535 and TA 100 in the presence of reduced nicotinamide adenine dinucleotide phosphate-fortified rat or mouse liver mitochondrial supernatant fractions. This mutagenic activity was inhibited strongly by cytochrome P-450 inhibitors. No mutagenic activity was observed for vinyl carbamate in the absence of added liver preparations or for ethyl carbamate in the presence or absence of liver fractions. Extensive tests with sensitive methods failed to detect vinyl carbamate as a metabolite of ethyl carbamate in the mouse in vivo. However, on administration of [ethyl-1-14C;1,2-3H]ethyl carbamate to adult mice the 3H/14C ratios of the hepatic DNA-, rRNA-, and protein-adducts were similar to each other and much lower than the ratio of the administered ethyl carbamate. These data are consistent with the presence of desaturated and/or oxidized ethyl groups in the macromolecular adducts. The qualitatively similar, but much stronger, carcinogenic activity of vinyl carbamate as compared to that of ethyl carbamate suggests that the metabolic pathways of these two carbamates may converge in the formation of similar or identical electrophilic reactants that bind covalently to macromolecules in vivo and initiate carcinogenesis.