Molecular Characteristics of Catechol Estrogen Quinones in Reactions with Deoxyribonucleosides

Abstract

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 (E1-3,4-Q), 17 beta-estradiol 3,4-quinone (E2-3,4-Q), or estrone 2,3-quinone (E1-2,3-Q) with deoxyguanosine (dG) or deoxyadenosine (dA) in CH3CO2H/H2O (1:1). Reaction of E1-3,4-Q or E2-3,4-Q with dG produced specifically 7-[4-hydroxyestron-1(alpha, beta)-yl]guanine (4-OHE1-1(alpha, beta)-N7Gua) or 7-[4-hydroxyestradiol-1(alpha, beta)-yl]-guanine (4-OHE2-1(alpha, beta)-N7Gua), respectively, in 40% yield, with loss of deoxyribose. These two quinones did not react with dA, deoxycytidine, or thymidine. When E1-2,3-Q was reacted with dG or dA, N2-(2-hydroxyestron-6-yl)deoxyguanosine (2-OHE1-6-N2dG, 10% yield) and N6-(2-hydroxyestron-6-yl)deoxyadenosine (2-OHE1-6-N6dA, 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.

Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

“…The synthetic procedure used for the preparation of the studied adducts from the different deuterated compounds was described in the literature [8]. Briefly, the 2-hydroxy derivatives of the deuterated compounds were prepared according to the method described by Gelbke et al [36].…”

“…The deuterated quinones were prepared by oxidation in acetonitrile at Ϫ40°C of the corresponding catechols using activated manganese dioxide utilizing a procedure published by Abul-Hajj et al [37]. The resulting suspension was then filtered directly into a stirred solution of dG as previously described [8] and let to react 5 h at room temperature.…”

“…If those preventive pathways are not completed, catechol estrogens can undergo further metabolic activation steps to quinones, highly electrophilic species that can covalently bind to nucleophilic groups, via Michael addition reactions [2, 6 -8]. In particular, the adduction of catechol estrogens to DNA bases [2,7,8] is known to induce mutations [9,10] that may initiate cancer [1,2]. The major protective pathway against this process is the reaction with glutathione [4,[11][12][13] yielding conjugates which can be easily excreted.…”

“…In previous works [34], the resulting products from the reactivity of estradiol-2,3-quinone towards desoxyribonucleosides have been investigated using LC-ESI-MS n . Depending upon the sites of both the DNA base and the steroid involved in the Michael addition process, several isomeric compounds were formed, in particular with dG which was found to be the most reactive deoxyribonucleoside [8,34]. Regio-and stereo-isomeric adducts have been identified using concomitant LC-ESI/MS n and NMR methodologies [35].…”

Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

“…On the other hand, generation of 4-hydroxylated CEs, particularly 4-hydroxylated estrone (4-OHE 1 ) is associated with the development of estrogensensitive cancers via metabolic redox cycling [17,18]. One possible mechanism for the genotoxicity of the catechol estrogens is the generation of electrophilic metabolites that react with DNA to form depurinating DNA adducts, which ultimately leads to cancer [19].…”