Reactions of formaldehyde plus acetaldehyde with deoxyguanosine and DNA: Formation of cyclic deoxyguanosine adducts and formaldehyde cross-links
Reactions of formaldehyde plus acetaldehyde with deoxyguanosine and DNA: Formation of cyclic deoxyguanosine adducts and formaldehyde cross-links
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DOI：
10.1021/tx025614r
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发表时间：
2003-02-01
影响因子：
4.1
通讯作者：
Hecht, SS
中科院分区：
文献类型：
--
作者：
Cheng, G;Shi, YL;Hecht, SS
我们研究了甲醛和乙醛与dGuo和DNA的反应，以确定是否可以形成某些1，N-2-丙氧基-dGuo加合物。这些加合物-3-（2 ′-脱氧核糖基）-5，6，7，8-四氢-8-羟基嘧啶并[1，2-a]嘌呤-（3 H）-酮（1）和3-（2 ′-脱氧核糖基）-5，6，7，8-四氢-6-羟基嘧啶并[1，2-a]嘌呤-（3 H）-酮（3a，B）-先前已被表征为丙烯醛与dGuo和DNA反应的产物。加合物1在某些模型脂质过氧化系统中占优势[Pan，J.，和Chung，F. L.（2002）Chem. Res. Toxicol. 15，367-372]。我们假设这可能是由于甲醛和乙醛与dGuo的逐步反应，而不是丙烯醛与dGuo的反应。结果表明，加合物1和3a，B是甲醛和乙醛与dGuo反应的相对较少的产物，并且它们的形成没有选择性。这些发现并不支持我们的假设。然而，大量的以前未知的环状dGuo加合物被确定在这个反应。新的加合物经MS、UV和NMR光谱表征为3-（2 '-脱氧核糖基）-6-甲基-1，3，5-二嗪烷[4，5-a]嘌呤-10（3 H）-酮（10a，B）的非对映异构体。加合物10 a，B是通过甲醛与N-2-亚乙基-dGuo的N1加成，然后环合而形成的。在乙醛与dGuo反应中形成了类似的3-（2 '-脱氧核糖基）-6，8-二甲基-1，3，5-二氮杂环己烷[4，5-a]嘌呤-10（3 H）酮（12 a-d）的四种非对映异构体。这些产物是嘧啶并[1，2-a]嘌呤型环外dGuo加合物的第一个例子，其中氧原子被掺入环外环中。甲醛衍生的加合物是甲醛加乙醛与dGuo反应的其他主要产物。其中突出的是N-2-羟甲基-dGuo（9）和交联二-（N-2-脱氧愈创木糖基）甲烷（13）。我们没有检测到加合物1，3a，B，或10a，B在酶水解的DNA已被允许与甲醛和乙醛反应。然而，我们确实检测到大量的甲醛交联二-（N-6-脱氧腺苷）甲烷（17），以及较少量的（N-6-脱氧腺苷-N-2-脱氧鸟苷）甲烷（18）、二-（N-2-脱氧鸟苷）甲烷（13）和N-6-羟甲基-dAdo（19）。在这些反应中还检测到甲醛和乙醛的席夫碱加合物。这些结果表明，甲醛加乙醛与dGuo的反应主要由新鉴定的环状加合物和甲醛衍生的产物，而与DNA的反应导致甲醛交联加合物的形成。致癌物质甲醛和乙醛在人体和环境中大量存在。因此，需要进一步的研究来确定本文所述的加合物是否在接触这些物质的动物或人类中形成。
We investigated the reactions of formaldehyde plus acetaldehyde with dGuo and DNA in order to determine whether certain 1,N-2-propano-dGuo adducts could be formed. These adducts-3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-(3H)-one (1) and 3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-6-hydroxypyrimido[1,2-a]purine-(3H)-one (3a,b)-have been previously characterized as products of the reaction of acrolein with dGuo and DNA. Adduct 1 predominates in certain model lipid peroxidation systems [Pan, J., and Chung, F. L. (2002) Chem. Res. Toxicol. 15, 367-372]. We hypothesized that this could be due to stepwise reactions of formaldehyde and acetaldehyde with dGuo, rather than by reaction of acrolein with dGuo. The results demonstrated that adducts 1 and 3a,b were relatively minor products of the reaction of formaldehyde and acetaldehyde with dGuo and that there was no selectivity in their formation. These findings did not support our hypothesis. However, substantial amounts of previously unknown cyclic dGuo adducts were identified in this reaction. The new adducts were characterized by their MS, UV, and NMR spectra as diastereomers of 3-(2'-deoxyribosyl)-6-methyl-1,3,5-diazinan[4,5-a]purin-10(3H)-one (10a,b). Adducts 10a,b were apparently formed by addition of formaldehyde to N1 of N-2-ethylidene-dGuo, followed by cyclization. An analogous set of four diastereomers of 3-(2'-deoxyribosyl)-6,8-dimethyl-1,3,5-diazinan[4,5-a]purin-10(3H)one (12a-d) were formed in the reactions of acetaldehyde with dGuo. These products are the first examples of exocyclic dGuo adducts of the pyrimido[1,2-a]purine type in which an oxygen atom is incorporated into the exocyclic ring. Formaldehyde-derived adducts were the other major products of the reactions of formaldehyde plus acetaldehyde with dGuo. Prominent among these were N-2-hydroxymethyl-dGuo (9) and the cross-link di-(N-2-deoxyguaonosyl)methane (13). We did not detect adducts 1, 3a,b, or 10a,b in enzymatic hydrolysates of DNA that had been allowed to react with formaldehyde plus acetaldehyde. However, we did detect substantial amounts of the formaldehyde cross-links di-(N-6-deoxyadenosyl)methane (17), with lesser quantities of (N-6-deoxyadenosyl-N-2-deoxyguanosyl)methane (18), di-(N-2-deoxyguanosyl)methane (13), and N-6-hydroxymethyl-dAdo (19). Schiff base adducts of formaldehyde and acetaldehyde were also detected in these reactions. These results demonstrate that the reactions of formaldehyde plus acetaldehyde with dGuo are dominated by newly identified cyclic adducts and formaldehyde-derived products whereas the reactions with DNA result in the formation of formaldehyde cross-link adducts. The carcinogens formaldehdye and acetaldehyde occur in considerable quantities in the human body and in the environment. Therefore, further research is required to determine whether the adducts described here are formed in animals or humans exposed to these agents.