DNA Cross-Linking By Diepoxybutane

二环氧丁烷 DNA 交联

• 批准号: 9381708
• 负责人: NATALIA Y TRETYAKOVA
• 金额: $ 34.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381708
• 关键词: 1,3-Butadiene; Animals; Automobile Exhaust; Binding; Biological; Blood; Butadiene; Butylene Glycols; Carbohydrates; Carbon; Carcinogens; Cell Culture Techniques; Cells; Chemicals; DNA; DNA Adducts; DNA Damage; DNA Repair; DNA biosynthesis; DNA lesion; Development; Diet; Environmental Exposure; Environmental Pollutants; Epoxy Compounds; Exposure to; FAPy; Fapy-dG; Fire - disasters; Funding; Genomic DNA; Glycols; Goals; Guanine; Hematologic Neoplasms; Human; Imidazole; Individual; Industrialization; Investigation; Isotope Labeling; Laboratories; Laboratory Animals; Lesion; Malignant Neoplasms; Mass Spectrum Analysis; Measurable; Mediating; Metabolic; Methodology; Modeling; Molecular; Molecular Structure; Mutagenesis; Mutagens; Occupational; Pharmaceutical Preparations; Population; Positioning Attribute; Procedures; Property; Proteins; Proteomics; Publications; Purines; Pyrimidine; Research; Risk; Risk Assessment; Role; Site; Smoke; Source; Structure; Techniques; Testing; Time; Tissues; Uncertainty; Urine; Work; adduct; base; cancer risk; carbohydrate metabolism; carcinogenicity; cigarette smoking; crosslink; cytotoxicity; environmental chemical; epidemiology study; erythritol anhydride; erythrose; forest; genotoxicity; improved; in vivo; innovation; insight; leukemia; lifestyle factors; novel; nucleobase; repaired; success

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.

摘要 1，3-丁二烯（丁二烯）是一种已知的人类致癌物质，在工业上生产，也存在于 汽车尾气、香烟烟雾和森林火灾。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-1-丁烯（EB）和3，4-环氧-1，2-丁二醇（EB-二醇）， 被认为是BD的最终遗传毒性物种。这些环氧化物优先修饰 在DNA中的N7-鸟嘌呤位置产生N7-（2-羟基-3，4-环氧丁烯-1-基）-鸟嘌呤（EB-1）。 Gua I）、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-N7 G-丁二醇交联（双-N7 G-BD）。这些N7-鸟嘌呤加合物是 水解不稳定，从DNA中缓慢释放，产生脱嘌呤位点。我们的研究在 上一个资助期检测到可测量数量的EB-瓜和THB-瓜 加合物在未处理的细胞，实验室动物和人类没有已知的暴露于BD。我们 还表明EB-瓜加合物可以自发地转化为稳定的2-羟基-3，4- 环氧丁-1-基-FAPy-dG（EB-FAPy）加合物。我们研究的长期目标是建立 BD发挥其遗传毒性和致癌作用的分子机制。的 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DNA损伤相同， 内源性来源如碳水化合物 新陈代谢.我们进一步提出丁二烯衍生的FAPy加合物有助于 丁二烯的致癌性和致突变性。我们建议的研究将改善 目前对致突变和细胞毒性机制的理解， 丁二烯暴露和提供新的见解内源性形成的DNA的起源 减少暴露人群癌症风险评估的不确定性。