Ornstein R L, Rein R
Chem Biol Interact. 1980 Apr;30(1):87-103. doi: 10.1016/0009-2797(80)90117-9.
The carcinogen 4-nitroquinoline 1-oxide (4NQO) and its metabolites undergo intercalative or covalent binding with DNA. Recent evidence indicates that the latter binding pattern is probably facilitated by an initial weaker intercalative interaction that can align potentially reactive sites on a 4NQO-metabolite and adjacent stacked bases. In the present study, we have proposed numerous possible covalent reaction products between 4NQO and its metabolites with DNA mini-helices based on chemical properties and key 'short-contacts' after energy-minimization in 21 different intercalative-like complexes. It is known from numerous experimental studies that 90% of the quinoline-bound DNAs in vivo involve guanine with the remaining 10% apparently involving adenine residues. The results of the present study suggest that this trend is not due to the greater affinity of the quinolines for guanine, but instead results from secondary processes involving the preferential formation of apurinic sites at aralkyl-adenine residues over that of aralkyl-guanine residues. In addition, observed mutational patterns can be rationalized in terms of the proposed reaction-products. The role of DNA repair mechanisms in the removal and correction of the different proposed reaction products are discussed. The binding pattern of several other aromatic carcinogens are similar to those depicted in the present work for the 4NQO-metabolites; hence the present study may be of some general significance.
致癌物4-硝基喹啉1-氧化物（4NQO）及其代谢产物与DNA发生嵌入或共价结合。最近的证据表明，后一种结合模式可能是由最初较弱的嵌入相互作用促进的，这种相互作用可以使4NQO代谢产物上潜在的反应位点与相邻的堆积碱基对齐。在本研究中，我们根据21种不同嵌入样复合物能量最小化后的化学性质和关键“短接触”，提出了4NQO及其代谢产物与DNA小螺旋之间许多可能的共价反应产物。从大量实验研究中可知，体内90%的喹啉结合DNA涉及鸟嘌呤，其余10%显然涉及腺嘌呤残基。本研究结果表明，这种趋势并非由于喹啉对鸟嘌呤的亲和力更高，而是由于涉及芳烷基腺嘌呤残基上优先形成脱嘌呤位点的二级过程，而不是芳烷基鸟嘌呤残基。此外，观察到的突变模式可以根据提出的反应产物进行合理解释。讨论了DNA修复机制在去除和纠正不同提出的反应产物中的作用。其他几种芳香族致癌物的结合模式与本研究中描述的4NQO代谢产物的结合模式相似；因此，本研究可能具有一定的普遍意义。
