Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides
Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides
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DOI：
10.1021/tx960002q
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发表时间：
1996-07-01
影响因子：
4.1
通讯作者：
Cavalieri, EL
中科院分区：
文献类型：
--
作者：
Stack, DE;Byun, J;Cavalieri, EL
雌激素在诱发癌症中有两个作用：通过受体介导的过程刺激细胞增殖，以及产生可以共价结合DNA的亲电子物质。后一种作用被认为是通过儿茶酚雌激素代谢物进行的，儿茶酚雌激素代谢物可以被氧化成与DNA结合的邻醌。雌酮3，4-醌（E（1）-3，4-Q）、17 β-雌二醇3，4-醌（E（2）-3，4-Q）、雌酮2，3-醌（E（1）-2，3-Q）分别与脱氧鸟苷（dG）或脱氧腺苷（dA）在CH_3CO_2H/H_2O（1：1）中反应，合成了4种雌激素-脱氧核苷加合物。E（1）-3，4-Q或E（2）-3，4-Q与dG反应，特异性产生7-[4-羟基雌二醇-1（α，β）-基]鸟嘌呤（4-OHE（1）-1（α，β）-N7 Gua）或7-[4-羟基雌二醇-1（α，β）-基]-鸟嘌呤（4-OHE（2）-1（α，β）-N7 Gua），产率分别为40%，但损失了脱氧核糖。这两个醌不与dA，脱氧胞苷，或胸苷反应。当E（1）-2，3-Q与dG或dA反应时，分别形成N-2-（2 -羟基雌酮-6-基）脱氧鸟苷（2-OHE（1）-6-N（2）dG，10%产率）和N-6-（2-羟基雌酮-6-基）脱氧腺苷（2-OHE（1）-6-N（6）dA，80%产率）。这些加合物提供了深入了解邻苯二酚雌激素的邻醌可能引起的DNA损伤类型。雌激素3，4-醌预计会产生脱嘌呤鸟嘌呤加合物，这些加合物从DNA中丢失，产生脱嘌呤位点，而2，3-醌会形成稳定的加合物，除非修复，否则这些加合物会保留在DNA中。本文报道的加合物将作为研究的参考，以阐明在生物系统中的雌激素加合物的结构。
Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can covalently bind to DNA. The latter role is thought to proceed through catechol estrogen metabolites, which can be oxidized to o-quinones that bind to DNA. Four estrogen-deoxyribonucleoside adducts were synthesized by reaction of estrone 3,4-quinone (E(1)-3,4-Q), 17 beta-estradiol 3,4-quinone (E(2)-3,4-Q), or estrone 2,3-quinone (E(1)-2,3-Q) with deoxyguanosine (dG) or deoxyadenosine (dA) in CH3CO2H/H2O (1:1). Reaction of E(1)-3,4-Q or E(2)-3,4-Q with dG produced specifically 7-[4-hydroxyestradiol-1(alpha,beta)-yl]guanine (4-OHE(1)-1(alpha,beta)-N7Gua) or 7-[4-hydroxyestradiol-1(alpha,beta)-yl]-guanine (4-OHE(2)-1(alpha,beta)-N7Gua), respectively, in 40% yield, with loss of deoxyribose. These two quinones did not react with dA, deoxycytidine, or thymidine. When E(1)-2,3-Q was reacted with dG or dA, N-2-(2 -hydroxyestron-6-yl)deoxyguanosine (2-OHE(1)-6-N(2)dG, 10% yield) and N-6-(2-hydroxyestron-6-yl)deoxyadenosine (2-OHE(1)-6-N(6)dA, 80% yield), respectively, were formed. These adducts provide insight into the type of DNA damage that can be caused by o-quinones of the catechol estrogens. The estrogen 3,4-quinones are expected to produce depurinating guanine adducts that are lost from DNA, generating apurinic sites, whereas the 2,3-quinones would form stable adducts that remain in DNA, unless repaired. The adducts reported here will be used as references in studies to elucidate the structure of estrogen adducts in biological systems.