Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Chem Res Toxicol. 2011 Jun 20;24(6):809-17. doi: 10.1021/tx200009b. Epub 2011 Apr 13.
1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen. The mechanism of BD-mediated cancer is of significant interest because of the widespread exposure of humans to BD from cigarette smoke and urban air. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is a highly genotoxic and mutagenic bis-alkylating agent believed to be the ultimate carcinogenic species of BD. We have previously identified several types of DEB-specific DNA adducts, including bis-N7-guanine cross-links (bis-N7-BD), N(6)-adenine-N7-guanine cross-links (N(6)A-N7G-BD), and 1,N(6)-dA exocyclic adducts. These lesions were detected in tissues of laboratory rodents exposed to BD by inhalation ( Goggin et al. (2009) Cancer Res. 69 , 2479 -2486 ). In the present work, persistence and repair of bifunctional DEB-DNA adducts in tissues of mice and rats exposed to BD by inhalation were investigated. The half-lives of the most abundant cross-links, bis-N7G-BD, in mouse liver, kidney, and lungs were 2.3-2.4 days, 4.6-5.7 days, and 4.9 days, respectively. The in vitro half-lives of bis-N7G-BD were 3.5 days (S,S isomer) and 4.0 days (meso isomer) due to their spontaneous depurination. In contrast, tissue concentrations of the minor DEB adducts, N7G-N1A-BD and 1,N(6)-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t(1/2) of 36-42 days. No differences were observed between DEB-DNA adduct levels in BD-treated wild type mice and the corresponding animals deficient in methyl purine glycosylase or the Xpa gene. Our results indicate that DEB-induced N7G-N1A-BD and 1,N(6)-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure.
1,3-丁二烯（BD）是一种重要的工业和环境化学物质，被归类为人类致癌物。BD 介导癌症的机制引起了广泛关注，因为人类从香烟烟雾和城市空气中广泛接触 BD。BD 经代谢激活为 1,2,3,4-二环氧丁烷（DEB），这是一种高度遗传毒性和致突变性的双烷基化剂，被认为是 BD 的最终致癌物质。我们之前已经鉴定出几种类型的 DEB 特异性 DNA 加合物，包括双-N7-鸟嘌呤交联（双-N7-BD）、N（6）-腺嘌呤-N7-鸟嘌呤交联（N（6）A-N7G-BD）和 1，N（6）-dA 外切加合物。这些损伤在通过吸入暴露于 BD 的实验室啮齿动物的组织中被检测到（Goggin 等人，（2009）Cancer Res. 69,2479-2486）。在本工作中，研究了通过吸入暴露于 BD 的小鼠和大鼠组织中双功能 DEB-DNA 加合物的持久性和修复。在小鼠肝、肾和肺中最丰富的交联物双-N7G-BD 的半衰期分别为 2.3-2.4 天、4.6-5.7 天和 4.9 天。由于自发脱嘌呤作用，双-N7G-BD 的体外半衰期为 3.5 天（S，S 异构体）和 4.0 天（meso 异构体）。相比之下，在实验过程中，次要的 DEB 加合物 N7G-N1A-BD 和 1，N（6）-HMHP-dA 的组织浓度基本不变，估计 t（1/2）为 36-42 天。BD 处理的野生型小鼠和相应的缺乏甲基嘌呤糖苷酶或 Xpa 基因的小鼠中 DEB-DNA 加合物水平没有差异。我们的结果表明，DEB 诱导的 N7G-N1A-BD 和 1，N（6）-HMHP-dA 加合物在体内持续存在，可能导致 BD 暴露引起的突变和癌症。
