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.
Morgan
P
P
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Maggs
J L
JL
Bulman-Page
P C
PC
Hussain
F
F
Park
B K
BK
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D008658:Inactivation, Metabolic; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains
D005965:Glucuronates; C037475:2-fluoroestradiol; C037810:4-fluoroestradiol; D004958:Estradiol