Park K K, Liem A, Stewart B C, Miller J A
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706.
Carcinogenesis. 1993 Mar;14(3):441-50. doi: 10.1093/carcin/14.3.441.
Vinyl carbamate epoxide (VCO) was found to possess strong electrophilic, mutagenic and carcinogenic activities. It reacted with water at 37 degrees C and pH 7.4 (phosphate buffer) to form glycolaldehyde and several related reducing compounds; none of these products were mutagenic for Salmonella typhimurium TA1535. Under these conditions VCO had a half-life (determined chemically and mutagenically) of approximately 10.5 min. This half-life was progressively lowered by increasing concentrations of chloride ion (liver, serum and isotonic levels). This ion reacted with VCO to form chloroacetaldehyde. VCO also reacted with other nucleophiles such as glutathione, DNA and its constituent guanine and adenine bases. The purine adducts formed by VCO in DNA in vitro and in vivo were released by weak acid treatment and consisted of 7-(2'-oxoethyl)guanine and N2,3-ethenoguanine as major products with 1,N6-ethenoadenine as a minor product. VCO was a strong direct mutagen in Salmonella typhimurium TA1535 and TA100 but was only weakly active in the TA98 mutant. VCO was a stronger initiator of carcinogenesis in the skin of CD-1 mice and in the liver of infant male B6C3F1 mice than its metabolic precursors vinyl carbamate (VC) and ethyl carbamate (EC). Unlike VC and EC, VCO was a strong complete carcinogen in the skin of CD-1 mice and induced papillomas and carcinomas following repetitive administration of sub-ulcerogenic doses. VCO also exhibited some carcinogenic activity in the lungs of mice and in the s.c. and mammary tissue of female Sprague-Dawley rats. These data and those from other recent studies support the conclusion that VCO is a major strong electrophilic, mutagenic and carcinogenic metabolite of EC and VC in the mouse.
氨基甲酸乙烯酯环氧化物（VCO）被发现具有很强的亲电、诱变和致癌活性。它在37℃和pH 7.4（磷酸盐缓冲液）条件下与水反应，生成乙醇醛和几种相关的还原性化合物；这些产物对鼠伤寒沙门氏菌TA1535均无致突变性。在这些条件下，VCO的半衰期（通过化学和诱变方法测定）约为10.5分钟。随着氯离子浓度（肝脏、血清和等渗水平）的增加，该半衰期逐渐缩短。氯离子与VCO反应生成氯乙醛。VCO还与其他亲核试剂如谷胱甘肽、DNA及其组成成分鸟嘌呤和腺嘌呤碱基发生反应。VCO在体外和体内DNA中形成的嘌呤加合物经弱酸处理后释放出来，主要产物为7-（2'-氧代乙基）鸟嘌呤和N2,3-乙烯基鸟嘌呤，次要产物为1,N6-乙烯基腺嘌呤。VCO在鼠伤寒沙门氏菌TA1535和TA100中是一种强直接诱变剂，但在TA98突变体中活性较弱。与它的代谢前体氨基甲酸乙烯酯（VC）和氨基甲酸乙酯（EC）相比，VCO在CD-1小鼠皮肤和雄性幼龄B6C3F1小鼠肝脏中是更强的致癌引发剂。与VC和EC不同，VCO在CD-1小鼠皮肤中是一种强完全致癌物，重复给予亚溃疡剂量后可诱发乳头状瘤和癌。VCO在小鼠肺以及雌性Sprague-Dawley大鼠的皮下和乳腺组织中也表现出一定的致癌活性。这些数据以及其他近期研究的数据支持以下结论：VCO是小鼠体内EC和VC的主要强亲电、诱变和致癌代谢产物。
