title: Estrogen-nucleic acid adducts: reaction of 3,4-estrone o-quinone with nucleic acid bases.
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(alpha,beta)-yl]thymine, N4-(4-hydroxyestrone-1- yl)cytosine, and N4-(4-hydroxy- estrone-2-yl)cytosine. No reaction products were obtained with guanine presumably due to poor solubility in DMF.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
authors.forename: A
authors.initials: A
authors.lastname: Akanni
authors.forename: K
authors.initials: K
authors.lastname: Tabakovic
authors.forename: Y J
authors.initials: YJ
authors.lastname: Abul-Hajj
mesh_terms: D003853:Deoxyribonucleosides / Q000737:chemistry*; D004963:Estrenes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D003853:Deoxyribonucleosides; D004963:Estrenes; C044208:1,5(10)-estradiene-3,4,17-trione