MACROMOLECULAR BINDING OF ESTROGENS AND CARCINOGENESIS

这些研究的目的是确定亲电性 邻苯二酚合成过程中雌二醇代谢产物的研究 雌激素(1，2-和4，5-环氧化物)及其进一步的代谢产物 邻苯二酚类雌激素(2，3-和3，4-O-半喹酮和邻苯二酚) 是参与大分子结合的活性中间体。至 为此，我们将合成未标记的和三标记的 雌烯醇酮1，2-和4，5-环氧化物和2，3-和3，4-雌激素-o- (A)研究这些化合物的共价结合 化合物在体外对Poly G、Poly A、DNA、RNA和蛋白质的作用。 (B)调查是否在腹膜腔内注射氚 标记雌二醇、2-羟基雌二醇和4-羟基雌二醇 结果与仓鼠的肾、肝和肺发生共价结合 蛋白质和核酸，(C)决定类似的结合是否 这些化合物中的一种是使用C3H/10T1/2细胞培养的，(D) 确定这些化合物是否能够诱导细胞 利用C3H/10T1/2和叙利亚仓鼠胚胎细胞进行转化， (E)确定这些化合物是否能够诱导 使用Ames沙门氏菌试验的突变和(F)尝试 从细胞培养中分离的加合物(~3H标记)的鉴定 和体外孵化。提纯的加合物将是 用质谱仪和高分辨率核磁共振对其进行了表征。 此外，加合物将与标准的 亲电性化合物的化学合成 含有简单氨基酸和核苷的雌激素代谢物。

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.