OXIDATIVE DEHALOGENATION OF 2-FLUORO-17-ALPHA-ETHYNYLOESTRADIOL INVIVO - A DISTAL STRUCTURE-METABOLISM RELATIONSHIP OF 17-ALPHA-ETHYNYLATION

Metabolic activation to catechols and their oxidation products is variously considered to contribute to the genotoxic, cytotoxic, transforming and tumour-promoting activities of exogenous steroidal oestrogens. 2-Fluoro-17alpha-ethynyloestradiol (2-FEE2) Was synthesized as a prototype of pharmacologically active derivatives of 17beta-oestradiol which are resistant to metabolic activation in vivo. It possessed high affinity for the rat uterine oestrogen receptor and was oestrogenic in rats. Biliary metabolites of [6,7-H-3]2-FEE2 (0.73 mumol/kg, 157 mug/kg, i.v.) in female rats were characterized: 87% of the radiolabel was excreted, principally as 2-FEE, glucuronide, over 6 hr. Although 2-fluoro- 17beta-oestradiol is not metabolized to C-2 oxygenated products in vivo, 2-FEE, underwent rapid and appreciable oxidative defluorination. 2-Hydroxy-17alpha-ethynyloestradiol and 2-methoxy-17alpha-ethynyloestradiol represented, respectively, 8% and 13% of the dose. Fluorination nevertheless restricted C2 oxygenation to ca. 28% of that which 17alpha-ethynyloestradiol undergoes in female rats. C-4 oxygenation of 2-FEE2, resulting in catechol formation, occurred but to a lesser extent (ca. 12% of dose). None of the major and identified minor biliary metabolites was a product of metabolic activation at the ethynyl function. A mechanistic rationalization of the long range enhancement by 17alpha-ethynylation of oxidative defluorination at C-2 is presented.