The formation and biological significance of N7-guanine adducts.
The formation and biological significance of N7-guanine adducts.
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DOI：
10.1016/j.mrgentox.2009.05.006
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发表时间：
2009-08
影响因子：
1.9
通讯作者：
Swenberg, James A.
中科院分区：
文献类型：
--
作者：
Boysen, Gunnar;Pachkowski, Brian F.;Nakamura, Jun;Swenberg, James A.
DNA烷基化或加合物的形成发生在DNA的亲核位点，主要是鸟嘌呤的N7位。自从第一个N7-鸟嘌呤加合物的鉴定以来，已经报道了数百个关于DNA加合物的研究。解决的主要问题包括N7-鸟嘌呤加合物和暴露，诱变和其他生物学终点之间的关系。N7-鸟嘌呤加合物经常形成，但可能具有最小的生物学相关性，因为它们在化学上不稳定，并且不参与沃森克里克碱基配对。然而，N7-鸟嘌呤加合物已被证明是内部暴露于直接作用和代谢活化的致癌物的极好的生物标志物。然而，关于N7-鸟嘌呤加合物的生物学意义出现了问题，这些加合物容易形成，不持久，并且不太可能具有致突变性。因此，我们着手审查目前的文献，以评估其形成和参与诱变或其他生物过程中的N7-鸟嘌呤加合物的机制证据。得出的结论是，没有足够的证据表明N7-鸟嘌呤加合物可用于确认靶组织暴露和证明分子剂量之外。几乎没有证据表明N7-鸟嘌呤加合物或其脱嘌呤产物脱嘌呤位点是细胞和组织突变的原因，因为除非毒性存在，否则AP位点的增加尚未显示。然而，需要更多的研究来确定化学脱嘌呤与DNA修复蛋白去除的程度。有趣的是，N7-鸟嘌呤加合物明显作为内源性背景加合物存在，并且内源性背景量似乎随年龄增加而增加。此外，N7-鸟嘌呤加合物已显示转化为开环损伤（FAPy），其更持久并且具有更高的致突变效力。人体研究的样本量有限，对照组和研究组之间的差异很小。未来的研究应涉及大量个体的人体研究，分析应包括相应的开环FAP y衍生物。
DNA alkylation or adduct formation occurs at nucleophilic sites in DNA, mainly the N7-position of guanine. Ever since identification of the first N7-guanine adduct, several hundred studies on DNA adducts have been reported. Major issues addressed include the relationships between N7-guanine adducts and exposure, mutagenesis, and other biological endpoints. It became quickly apparent that N7-guanine adducts are frequently formed, but may have minimal biological relevance, since they are chemically unstable and do not participate in Watson Crick base pairing. However, N7-guanine adducts have been shown to be excellent biomarkers for internal exposure to direct acting and metabolically activated carcinogens. Questions arise, however, regarding the biological significance for N7-guanine adducts that are readily formed, do not persist, and are not likely to be mutagenic. Thus, we set out to review the current literature to evaluate their formation and the mechanistic evidence for the involvement of N7-guanine adducts in mutagenesis or other biological processes. It was concluded that there is insufficient evidence that N7-guanine adducts can be used beyond confirmation of exposure to the target tissue and demonstration of the molecular dose. There is little to no evidence that N7-guanine adducts or their depurination product, apurinic sites, are the cause of mutations in cells and tissues, since increases in AP sites have not been shown unless toxicity is extant. However, more research is needed to define the extent of chemical depurination versus removal by DNA repair proteins. Interestingly, N7-guanine adducts are clearly present as endogenous background adducts and the endogenous background amounts appear to increase with age. Furthermore, the N7-guanine adducts have been shown to convert to ring opened lesions (FAPy), which are much more persistent and have higher mutagenic potency. Studies in humans are limited in sample size and differences between controls and study groups are small. Future investigations should involve human studies with larger numbers of individuals and analysis should include the corresponding ring opened FAPy derivatives.
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影响因子：
2.4
作者：
Bartsch, H;Nair, J;Velic, I
通讯作者：
Velic, I
DOI：
10.1016/0027-5107(90)90173-2
发表时间：
1990-07-01
期刊：
MUTATION RESEARCH
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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