Structure-metabolism relationships of ring-A halogenated analogues of 17 alpha-ethynyloestradiol.

The metabolic fates of 2-chloro-, 2-bromo-, 4-bromo- and 2-iodo-17 alpha-ethynyloestradiol (EE2) in rats were determined. 6,7-3H-labelled analogues (0.1-2.0 mumol/kg) were administered i.v. to anaesthetized animals. The metabolites of all four compounds were rapidly and extensively excreted in bile (79-93% of the dose over 6 h). Unlike EE2 and 2-fluoro-EE2 (2-FEE2), neither 2-chloro(Cl)-(2.0 mumol/kg),2-bromo(Br)-(0.1 mumol/kg), nor 2-iodo(I)-EE2-(0.1 mumol/kg) underwent C-2 hydroxylation in female rats; 2-BrEE2 was similarly refractory in male rats; females, was subject to approx. 2-fold greater C-2 hydroxylation than 2-FEE2 but this equalled only approx. 60% of that undergone by EE2. All three of the C-2 halogenated derivatives were substantially excreted unchanged except for conjugation. 2-ClEE2 alone was C-4 hydroxylated to an appreciable extent. The oxidative metabolism of 2- and 4-BrEE2 in rats was sexually differentiated: 2-BrEE2 yielded an alkyl hydroxylated metabolite and a two-component dihydroxylated fraction in the ratio 1:0.09 and 1:0.76 in males and females, respectively; 4-BrEE2 underwent C-2 and alicyclic (C-15) hydroxylation in the ratio 1:4.8 and 1:0.07 in males and females, respectively. 2-ClEE2 formed much less alkyl monohydroxylated metabolite (C-16 hydroxylated for 2-Cl- and 2-IEE2) than did either 2-BrEE2 or 2-IEE2. The observed structure-metabolism relationships are discussed.

The metabolism of 2- and 4-fluoro-17 beta-oestradiol in the rat and its implications for oestrogen carcinogenesis.

2-Fluoro-[6,7-3H]17 beta-oestradiol([3H]2-FE2) and 4-fluoro-[6,7-3H]17 beta-oestradiol([3H]4-FE2) were synthesized by the fluorination and reduction of [3H]oestrone and purified by HPLC. [3H]2-FE2 and [3H]4-FE2 (72.5 micrograms/kg; 0.25 mumol/kg) were administered i.v. to anaesthetized female and male Wistar rats (N = 4) with biliary cannulae. Bile was collected for 6 hr. Female rats administered [3H]2-FE2 excreted 85% of the dose into bile over 6 hr whilst male rats excreted 77%. After the administration of [3H]4-FE2, female and male rats excreted 72 and 83% of dose into bile over 6 hr, respectively. The biliary metabolites were glucuronides in all cases. The principal metabolite of [3H]2-FE2 liberated from biliary conjugates by beta-glucuronidase was 2-fluoroestrone in both female rats (64% of dose) and male rats (57%). No 2-hydroxylated, i.e. oxidatively defluorinated, metabolites were detected in either sex. In contrast, 2-hydroxylation of [3H]4-FE2 did occur, but only in female rats: 2-hydroxy-4-fluoro-oestrone (22%) and 2-methoxy-4-fluoroestrone (17%) were identified as biliary aglycones. However, the major metabolite was 4-fluoroestrone (4FE1; 38%). In male rats, 4-FE1 and 4-fluoro D-ring-oxygenated products were the principal biliary aglycones. The differences in metabolism between the two fluoro analogues and oestradiol are discussed with particular reference to the possible involvement of 2- and 4-hydroxy (catechol) oestrogens in oestrogen toxicity.