Estrogen−Nucleic Acid Adducts: Reaction of 3,4-Estrone o-Quinone with Nucleic Acid Bases

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Abstract
Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. Previous studies have shown that 3,4-estrone quinone (3,4-EQ) can redox-cycle and is capable of inducing exclusively single-strand DNA breaks in MCF-7 breast cancer cells [Nutter et al. (1991) J. Biol. Chem.226, 16380−16386]. These studies, however, could not provide conclusive evidence about the mechanism of estrogen carcinogenesis. In order to explore this in more detail, we have shown previously that 3,4-EQ can react with adenine under electrochemical reductive conditions to yield an estrogen−nucleic acid adduct [Abul-Hajj et al. (1995) J. Am. Chem. Soc. 117, 6144−6145]. In this paper, we report the synthesis and identification of seven estrogen−nucleic acid adducts obtained from reaction of 3,4-EQ with adenine, thymine, and cytosine. Initial purification of reaction mixtures using TLC followed by HPLC gave sufficient quantities of reaction products for identification using 1H-NMR and mass spectral determinations. Reaction of 3,4-EQ with adenine, thymine, and cytosine gave the following estrogen−nucleic acid adducts: 8-(4-hydoxyestrone-1-yl)adenine, 3-adenylimino-1,5(10)-estradiene-4,17-dione, 4-adenylimino-1,5(10)-estradiene-3,17-dione, N1-[4-hydroxyestrone-1(α,β)-yl]thymine, N4-(4-hydroxyestrone-1-yl)cytosine, and N4-(4-hydroxyestrone-2-yl)cytosine. No reaction products were obtained with guanine presumably due to poor solubility in DMF.