Oxidative dehalogenation of 2-fluoro-17 alpha-ethynyloestradiol in vivo. A distal structure-metabolism relationship of 17 alpha-ethynylation

• Published in: Biochemical pharmacology Vol. 44; no. 9; p. 1717
• Main Authors: Morgan, P, Maggs, J L, Page, P C, Park, B K
• Format: Journal Article
• Language: English
• Published: England 03-11-1992
• Subjects: Animals; Bile - metabolism; Ethinyl Estradiol - analogs & derivatives; Ethinyl Estradiol - metabolism; Female; Halogens - metabolism; Hydroxylation; Oxidation-Reduction; Rats; Rats, Wistar; Receptors, Estrogen - metabolism; Structure-Activity Relationship; Uterus - drug effects; Uterus - metabolism; Uterus - ultrastructure; Vagina - drug effects
• ISSN: 0006-2952
• DOI: 10.1016/0006-2952(92)90064-P

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-17 alpha-ethynyloestradiol (2-FEE2) was synthesized as a prototype of pharmacologically active derivatives of 17 beta-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 [6,7-3H]2-FEE2 (0.73 mumol/kg, 157 micrograms/kg, i.v.) in female rats were characterized: 87% of the radiolabel was excreted, principally as 2-FEE2 glucuronide, over 6 hr. Although 2-fluoro-17 beta-oestradiol is not metabolized to C-2 oxygenated products in vivo, 2-FEE2 underwent rapid and appreciable oxidative defluorination. 2-Hydroxy-17 alpha-ethynyloestradiol and 2-methoxy-17 alpha-ethynyloestradiol represented, respectively, 8% and 13% of the dose. Fluorination nevertheless restricted C-2 oxygenation to ca. 28% of that which 17 alpha-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 17 alpha-ethynylation of oxidative defluorination at C-2 is presented.