OXIDATIVE TRANSFORMATION OF 2-HYDROXYESTRONE - STABILITY AND REACTIVITY OF 2,3-ESTRONE QUINONE AND ITS RELATIONSHIP TO ESTROGEN CARCINOGENICITY

The carcinogenicity of estrogens in rodents and man has been attribute d to either alkylation of cellular macromolecules and/or redox-cycling , generation of active radicals, and DNA damage. Metabolic activation of estradiol leading to the formation of catechol estrogens is believe d to be a prerequisite for its genotoxic effects. 4-Hydroxyestradiol, although not 2-hydproxyestradiol, is a potent inducer of tumors in ham sters. Previous studies have shown that 3,4-estrone quinone can redox- cycle and is capable of inducing exclusively single strand DNA breaks in MCF-7 breast cancer cells, as well as react with various nucleophil es (thiol, imidazole, amino, phenolate, and acetoxy) to give Michael a ddition products. These results support the possible involvement of 3, 4-catechol/quinone estrogens in estrogen's carcinogenicity. To explain the decreased carcinogenicity of 2-hydroxyestrogens, the reactions of 2,3-estrone quinone (2,3-EQ) with nucleophiles were investigated. Rea ctions of 4-methylimidazole with 2,3-EQ gave a complex mixture of prod ucts leadng to the formation of the catechol, C-O dimerization product , and a 1,6-Michael addition product identified as the 1-(4-methylimid azolo)-2-hydroxyestrone. Reactions of 2,3-EQ under mildly basic condit ions with either ethyl phenolate or acetate gave several products whic h were characterized as the C-O and C-C: dimers, catechol, and 3,5-dih ydroxy-1(10),3-estradiene-2,17-dione. No Michael addition products wer e detected under these experimental conditions. The same products were also observed during the synthesis of 2,3-EQ, which led us to postula te that the lack of carcinogenicity of 2-hydroxyestrogens may be relat ed to the increased reactivity and decreased stability of the quinone under physiological conditions. These results are contrasted with thos e obtained with 3,4-EQ which is much more stable and therefore could d iffuse from the site of formation to the target tissue. These results along with rapid methylation and clearance may be very likely explanat ions for the decreased carcinogenicity of 2-hydroxyestrogens.