MACROMOLECULAR BINDING OF ESTROGENS AND CARCINOGENESIS

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The purpose of these studies is to determine whether electrophilic metabolites of estradiol formed during synthesis of catechol estrogens (1, 2- and 4, 5-epoxides) and further metabolites of catechol estrogens (2, 3- and 3, 4-o-semiquinone and o-quinones) are active intermediates involved in macromolecular binding. To this end we will synthesize unlabeled and tritum labeled estrenolone 1, 2- and 4, 5-epoxides, and 2, 3- and 3,4-estrogen-o- quinones for (a) investigating the covalent binding of these compounds to Poly G, Poly A, DNA, RNA, and proteins in vitro. (b) investigate whether intraperitoneal administration of tritium labeled estradiol, 2-hydroxyestradiol and 4-hydorxyestradiol results in covalent binding to hamster kidney, liver and lung proteins and nucleic acids, (c) determine whether similar binding of these compounds is involved using C3H/10T1/2 cell culture, (d) determine if these compounds are capable of inducing cellular transformation using C3H/10T1/2 and Syrian hamster embryo cells, (e) determine if these compounds are capable of inducing mutations using the Ames Salmonella assay and (f) attempt at identification of adducts (3H-labeled) isolated from cell cultures and in vitro incubations. The purified adducts will be characterized using mass spectrometry and high resolution NMR. Furthermore, the adducts will be compared to standard compounds obtained by chemical synthesis of electrophilic estrogen metabolites with simple amino acids and nucleosides.