A Akanni, K Tabakovic, Y J Abul-Hajj
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
Chemical research in toxicology 1997 AprMetabolic 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.
A Akanni, K Tabakovic, Y J Abul-Hajj. Estrogen-nucleic acid adducts: reaction of 3,4-estrone o-quinone with nucleic acid bases. Chemical research in toxicology. 1997 Apr;10(4):477-81
PMID: 9114987
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