State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Centre for Eco-environmental Sciences and University of the Chinese Academy of Sciences, the Chinese Academy of Sciences, Beijing 100085, PR China.
Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
Environ Sci Technol. 2020 May 19;54(10):6244-6253. doi: 10.1021/acs.est.9b07886. Epub 2020 May 1.
Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. We found recently that halogenated quinones could enhance the decomposition of hydroperoxides independent of transition-metal ions and formation of the novel quinone enoxy/ketoxy radicals. Here, we show that the major oxidation product was 2-amino-5-[(2-deoxy-β-d--pentofuranosyl)amino]-4-imidazol-4-one (dIz) when the nucleoside 2'-deoxyguanosine (dG) was treated with tetrachloro-1,4-benzoquinone (TCBQ) and -butyl hydroperoxide (-BuOOH). The formation of dIz was markedly inhibited by typical radical spin-trapping agents. Interestingly and unexpectedly, we found that the generated quinone enoxy radical played a critical role in dIz formation. Using [N]-8-oxodG, dIz was found to be produced either directly from dG or through the transient formation of 8-oxodG. Based on these data, we proposed that the production of dIz might be through an unusual haloquinone-enoxy radical-mediated mechanism. Analogous results were observed in the oxidation of ctDNA by TCBQ/-BuOOH and when -BuOOH was substituted by the endogenously generated physiologically relevant hydroperoxide 13-hydroperoxy-9,11-octadecadienoic acid. This is the first report that halogenated quinoid carcinogens and hydroperoxides can induce potent oxidation of dG to the more mutagenic product dIz via an unprecedented quinone-enoxy radical-mediated mechanism, which may partly explain their potential carcinogenicity.
卤代醌类是一类致癌中间体，也是新发现的饮用水氯化消毒副产物。我们最近发现，卤代醌类可以在没有过渡金属离子的情况下增强过氧化物的分解，并形成新型醌氧基/酮氧基自由基。在这里，我们表明当核苷 2'-脱氧鸟苷（dG）与四氯-1,4-苯醌（TCBQ）和 -丁基过氧化物（-BuOOH）一起处理时，主要的氧化产物是 2-氨基-5-[(2-脱氧-β-d--戊呋喃糖基)氨基]-4-咪唑-4-酮（dIz）。典型的自由基捕获剂显著抑制了 dIz 的形成。有趣的是，出乎意料的是，我们发现生成的醌氧基自由基在 dIz 的形成中起着关键作用。使用 [N]-8-氧代-dG，发现 dIz 可以直接从 dG 产生，也可以通过 8-氧代-dG 的瞬时形成产生。基于这些数据，我们提出 dIz 的产生可能是通过一种不寻常的卤代醌-氧基自由基介导的机制。在 TCBQ/-BuOOH 氧化 ctDNA 以及用内源性产生的生理相关过氧化物 13-过氧-9,11-十八碳二烯酸替代 -BuOOH 时，观察到类似的结果。这是第一个报道卤代醌类致癌剂和过氧化物可以通过一种前所未有的醌氧基自由基介导的机制，将 dG 氧化为更具致突变性的产物 dIz 的报道，这可能部分解释了它们的潜在致癌性。
