Leithauser M T, Liem A, Stewart B C, Miller E C, Miller J A
McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison 53706.
Carcinogenesis. 1990 Mar;11(3):463-73. doi: 10.1093/carcin/11.3.463.
Previous studies from this laboratory showed that (i) vinyl carbamate (VC) was much more carcinogenic than ethyl carbamate (EC) and that both carbamates induced the same spectrum of tumors in mice and rats, (ii) adducts of [14C]- or [3H]1,N6-ethenoadenosine and [14C]- or [3H]3,N4-ethenocytidine e were formed in the hepatic RNA of infant male B6C3F1 mice administered [1-14C]ethyl or [1,2-3H]ethyl EC and (iii) VC formed much more of the 1,N6-ethenoadenosine (epsilon Ado) adduct in the hepatic RNA and the 7-(2-oxoethyl)-guanine adduct in the hepatic DNA of mice than did EC. By analogy to the similar results of earlier studies by other investigators on the related carcinogen vinyl chloride, the above data suggested that VC epoxide was a reactive electrophilic metabolite of these carbamates. In the present studies, VC, but not EC, was found to be oxidized by 3-chloroperbenzoic acid to a derivative that reacted with adenosine to form epsilon Ado. Far more of this etheno nucleoside was formed from VC than from EC when these carbamates were metabolized by cofactor-fortified mouse liver microsomes in the presence of adenosine. Sodium diethyldithiocarbamate strongly inhibited these microsomal reactions and the formation of epsilon Ado in the hepatic RNA of mice administered either carbamate. Likewise, the i.p. preadministration of deithyldithiocarbamate markedly inhibited the induction of tumors by single i.p. doses of EC or VC in the livers of infant male B6C3F1 mice and in the livers, lungs and Harderian glands of infant female B6C3F1 mice. This inhibitor also considerably reduced lung tumor induction by VC in adult female A/Jax mice. 2-(2,4-Dichloro-6-phenyl) phenoxyethyl amine, a cytochrome P450 inhibitor, reduced the carcinogenicity of low doses of EC but appeared to increase the carcinogenicity of low doses of VC. The mutagenicity of VC for Salmonella typhimurium TA1535 in the presence of a hepatic activating system was greatly reduced by these inhibitors. The data from all these studies are consistent with the proposal that VC epoxide is an ultimate electrophilic and carcinogenic metabolite of EC and VC in the mouse.
（i）氨基甲酸乙烯酯（VC）的致癌性远高于氨基甲酸乙酯（EC），且两种氨基甲酸盐在小鼠和大鼠中诱发的肿瘤谱相同；（ii）给雄性幼龄B6C3F1小鼠腹腔注射[1-14C]乙基或[1,2-3H]乙基EC后，其肝脏RNA中形成了[14C]-或[3H]1,N6-乙烯基腺苷以及[14C]-或[3H]3,N4-乙烯基胞苷的加合物；（iii）与EC相比，VC在小鼠肝脏RNA中形成的1,N6-乙烯基腺苷（εAdo）加合物以及在肝脏DNA中形成的7-(2-氧代乙基)-鸟嘌呤加合物更多。类比其他研究者早期对相关致癌物氯乙烯的类似研究结果，上述数据表明VC环氧化物是这些氨基甲酸盐的一种活性亲电代谢产物。在本研究中，发现VC能被3-氯过苯甲酸氧化成一种可与腺苷反应生成εAdo的衍生物，而EC则不能。当这些氨基甲酸盐在腺苷存在的情况下由添加了辅因子的小鼠肝脏微粒体代谢时，由VC形成的这种乙烯基核苷远比由EC形成的多。二乙基二硫代氨基甲酸钠强烈抑制这些微粒体反应以及给小鼠注射任一种氨基甲酸盐后其肝脏RNA中εAdo的形成。同样，腹腔注射二乙基二硫代氨基甲酸钠能显著抑制单次腹腔注射EC或VC对雄性幼龄B6C3F1小鼠肝脏以及雌性幼龄B6C3F1小鼠肝脏、肺和哈德氏腺肿瘤的诱发。这种抑制剂还能显著降低成年雌性A/Jax小鼠中VC对肺部肿瘤 的诱发。细胞色素P450抑制剂2-(2,4-二氯-6-苯基)苯氧基乙胺可降低低剂量EC的致癌性，但似乎会增加低剂量VC的致癌性。在肝脏活化系统存在的情况下，这些抑制剂可大大降低VC对鼠伤寒沙门氏菌TA1535的致突变性。所有这些研究的数据均支持以下观点：VC环氧化物是小鼠体内EC和VC的最终亲电致癌代谢产物。
