Oxidative dehalogenation of 2-fluoro-17 alpha-ethynyloestradiol in vivo. 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-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.
Morgan
P
P
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Maggs
J L
JL
Page
P C
PC
Park
B K
BK
D000818:Animals; D001646:Bile / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006219:Halogens / Q000378:metabolism*; D006900:Hydroxylation; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014621:Vagina / Q000187:drug effects
D006219:Halogens; D011960:Receptors, Estrogen; C078435:2-fluoro-17-ethynylestradiol; D004997:Ethinyl Estradiol