Reactions of Estradiol-2,3-quinone with Deoxyribonucleosides: Possible Insights in the Reactivity of Estrogen Quinones with DNA
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- 作者：Odile Convert ; Christel Van Aerden ; Laurent Debrauwer ; Estelle Rathahao ; Huguette Molines ; Franç ; oise Fournier ; Jean-Claude Tabet ; and Alain Paris
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：May 2002
- 年：2002
- 卷：15
- 期：5
- 页码：754 - 764
- 全文大小：149K
- 年卷期：v.15,no.5(May 2002)
- ISSN：1520-5010
文摘
Estrogen 2,3- and 3,4-quinones are reactive species toward nucleophiles and Michaelacceptors. As such, they can bind to DNA and induce cellular damages. As an alkylation model,reactions of estradiol-2,3-quinone with deoxyribonucleosides were previously studied by massspectrometry. In this work, estrogen-deoxyribonucleoside adducts were synthesized by reactionof 17
-estradiol-2,3-quinone with deoxyguanosine or deoxyadenosine and analyzed by NMRand LC-MSn in order to determine the structure and the stereochemistry of the resultingcovalent adducts. Although estradiol- and estrone-2,3-quinones were previously thought togive mainly stable adducts, identification of depurinating adducts with both nucleosides, i.e.,2-OHE2-6(
,)-N7Gua and 2-OHE2-6(,)-N7Ade, was unambiguously obtained. This is ofparticular interest since depurinating adducts are generated from DNA, and therefore, theiramount should be correlated to the parallel formation of apurinic sites, which might play animportant role in the cancer initiation process. Besides, a byproduct, i.e., 2-hydroxy-11-oxo-estradiol, corresponding to an unstable alkylation product of 2-hydroxyestradiol has beenunambiguously identified and is indicative of a plausible addition process at the C9 positionof catechol estrogens. The synthetic adducts will be useful as reference compounds to furtherelucidate the structure of adducts formed by reaction of estrogen metabolites with DNA oroligonucleotides.
-estradiol-2,3-quinone with deoxyguanosine or deoxyadenosine and analyzed by NMRand LC-MSn in order to determine the structure and the stereochemistry of the resultingcovalent adducts. Although estradiol- and estrone-2,3-quinones were previously thought togive mainly stable adducts, identification of depurinating adducts with both nucleosides, i.e.,2-OHE2-6(,)-N7Gua and 2-OHE2-6(,)-N7Ade, was unambiguously obtained. This is ofparticular interest since depurinating adducts are generated from DNA, and therefore, theiramount should be correlated to the parallel formation of apurinic sites, which might play animportant role in the cancer initiation process. Besides, a byproduct, i.e., 2-hydroxy-11-oxo-estradiol, corresponding to an unstable alkylation product of 2-hydroxyestradiol has beenunambiguously identified and is indicative of a plausible addition process at the C9 positionof catechol estrogens. The synthetic adducts will be useful as reference compounds to furtherelucidate the structure of adducts formed by reaction of estrogen metabolites with DNA oroligonucleotides.