Park K K, Sohn Y, Liem A, Kim H J, Stewart B C, Miller J A
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706, USA.
Carcinogenesis. 1997 Feb;18(2):431-7. doi: 10.1093/carcin/18.2.431.
The metabolism and mutagenicity of phenyl and 4-nitrophenyl vinyl ethers (PVE and NPVE) and their epoxide metabolites, phenoxyoxirane (PO) and 2'-(4-nitro-phenoxy)oxirane (NPO), were studied including reactions with DNA and tests for carcinogenicity. PVE and NPVE were epoxidized in dry acetone by dimethyldioxirane to give high yields (95%) of the pure epoxides. The epoxides are unstable in aqueous media and in 0.1 N phosphate buffer, pH 7.4, at 37 degrees C; they had half-lives of 2.7 min (PO) and 4.4 min (NPO). These times were reduced to 1.9 min (PO) and 2.5 min (NPO) in the presence of isotonic (154 mM) chloride ion. In neutral phosphate buffer these epoxides hydrolyze to form glycolaldehyde and the corresponding phenols; in the presence of chloride ion, chloroacetaldehyde and several unknown compounds are also formed. Glycolaldehyde was also found as a hydrolysis product of the presumed epoxides generated in the hepatic microsomal oxidation of PVE and NPVE. PO and NPO reacted with DNA to form adducts that depurinated in weak acid to form 7-(2'-oxoethyl)guanine and N(2),3-ethenoguanine. PO was weakly mutagenic in Salmonella typhimurium TA1535 while NPO was much more mutagenic under the same conditions. PO and NPO were found to have mutagenic half-lives that matched their chemical half-lives. PO and NPO were found to be tumorigenic in the skin of mice after single or five initiating doses followed by multiple doses of phorbol ester (TPA). NPO was a stronger tumor initiator than PO. NPO had appreciable activity as an initiator of hepatoma formation in infant male B6C3F1 mice. Thus PO and NPO are electrophilic, mutagenic and tumorigenic metabolites of their corresponding phenyl vinyl ethers.
研究了苯基乙烯基醚（PVE）和4 - 硝基苯基乙烯基醚（NPVE）及其环氧化代谢产物苯氧基环氧乙烷（PO）和2'-（4 - 硝基苯氧基）环氧乙烷（NPO）的代谢和致突变性，包括它们与DNA的反应及致癌性测试。PVE和NPVE在干燥丙酮中被二甲基二氧杂环丙烷环氧化，以高产率（95%）得到纯环氧化物。这些环氧化物在水性介质和0.1 N磷酸盐缓冲液（pH 7.4，37℃）中不稳定；它们的半衰期分别为2.7分钟（PO）和4.4分钟（NPO）。在等渗（154 mM）氯离子存在下，这些时间缩短至1.9分钟（PO）和2.5分钟（NPO）。在中性磷酸盐缓冲液中，这些环氧化物水解形成乙醇醛和相应的酚类；在氯离子存在下，还会形成氯乙醛和几种未知化合物。乙醇醛也是PVE和NPVE肝微粒体氧化过程中生成的假定环氧化物的水解产物。PO和NPO与DNA反应形成加合物，这些加合物在弱酸中脱嘌呤形成7 - （2'-氧代乙基）鸟嘌呤和N(2),3 - 乙烯基鸟嘌呤。PO在鼠伤寒沙门氏菌TA1535中具有弱致突变性，而NPO在相同条件下致突变性更强。发现PO和NPO的致突变半衰期与它们的化学半衰期相匹配。在单次或五次起始剂量后再给予多次佛波酯（TPA）处理后，发现PO和NPO在小鼠皮肤中具有致瘤性。NPO是比PO更强效的肿瘤起始剂。NPO在幼年雄性B6C3F1小鼠中作为肝癌形成的起始剂具有显著活性。因此，PO和NPO是其相应苯基乙烯基醚的亲电、致突变和致瘤代谢产物。
