DNA Cross-Linking By Diepoxybutane

摘要 1，3-丁二烯(丁二烯)是一种已知的人类致癌物质，工业生产，也在 汽车尾气、香烟烟雾和森林大火。丁二烯的环氧化物代谢物，即 1，2，3，4-二环氧丁烷(DEB)、3，4-环氧丁烯(EB)和3，4-环氧丁二醇(EB-二醇)； 被认为是BD的终极遗传毒性物种。这些环氧化物优先修饰 N7-鸟嘌呤在DNA中的位置，产生N7-(2-羟基-3，4-环氧丁烯-1-基)-鸟嘌呤(EB- N7-(1-羟基-3-丁烯-2-基)-鸟嘌呤(EB-GUA II)、N7-(三羟基丁基)鸟嘌呤(THB- Gua)和双-N7G-丁二醇交联物(bis-N7G-BD)。这些N7-鸟嘌呤加合物是 水解性不稳定，从DNA中缓慢释放，形成无嘌呤位点。我们内部的学习 上一个供资期间发现了可测量的EB-Gua和THB-Gua 未经处理的细胞、实验动物和人类中的加合物，没有已知接触BD的情况。我们 还表明EB-GUA加合物可以自发地转化为稳定的2-羟基-3，4- 环氧丁基-1-基-Fapy-DG(EB-Fapy)加合物。我们研究的长期目标是建立 BD引起遗传毒性和致癌作用的分子机制。这个 本研究的目的是阐明内源性THB-Gua的代谢/饮食来源 和EB-GUA加合物，并阐明EB-Fapy和THB-Fapy的遗传毒性作用 加合物。这项研究的中心假设是DNA损伤与产生的 接触丁二烯可由碳水化合物等内源形成 新陈代谢。我们进一步提出丁二烯衍生的Fapy加合物有助于 丁二烯的致癌和致突变特性。我们建议的研究将会改善 黄曲霉毒素致突变和细胞毒性机制的研究现状 丁二烯暴露，并为内源性DNA的起源提供了新的见解 减少暴露人群癌症风险评估的不确定性。

Abstract 1,3-butadiene (butadiene) is a known human carcinogen produced industrially and also found in automobile exhaust, cigarette smoke, and forest fires. Epoxide metabolites of butadiene, i.e. 1,2,3,4-diepoxybutane (DEB), 3,4-epoxy-1-butene (EB), and 3,4-epoxy-1,2-butanediol (EB-diol), are thought to be the ultimate genotoxic species of BD. These epoxides preferentially modify the N7-guanine position in DNA to give rise to N7- (2-hydroxy-3,4-epoxybutene-1-yl)-guanine (EB- Gua I), N7-(1-hydroxy-3-buten-2-yl)-guanine (EB-Gua II), N7-(trihydroxybutyl) guanine (THB- Gua), and bis-N7G-butanediol cross-links (bis-N7G-BD). These N7-guanine adducts are hydrolytically labile and are slowly released from DNA to give apurinic sites. Our studies within the previous funding period have detected measurable amounts of EB-Gua and THB-Gua adducts in untreated cells, laboratory animals, and humans with no known exposure to BD. We have also shown that EB-Gua adducts can be spontaneously converted to stable 2-hydroxy-3,4- epoxybut-1-yl-FAPy-dG (EB-FAPy) adducts. The long-range goal of our research is to establish the molecular mechanisms by which BD elicits its genotoxic and carcinogenic effects. The objective of this research is to elucidate the metabolic/dietary origins of endogenous THB-Gua and EB-Gua adducts and to elucidate the genotoxic effects of EB-FAPy and THB-FAPy adducts. The central hypothesis of this research is that DNA lesions identical to those generated by butadiene exposure can be formed by endogenous sources such as carbohydrate metabolism. We further propose that butadiene-derived FAPy adducts contribute to carcinogenic and mutagenic properties of butadiene. Our proposed studies will improve the current understanding of the mechanisms of mutagenesis and cytotoxicity resulting from butadiene exposure and afford new insights into the origins of endogenously formed DNA lesions, reducing the uncertainty in cancer risk assessment in exposed populations.