The metabolism of 2,4-dibromo [6,7-3H]17 beta-oestradiol in the rat: ring-A dibromination blocks male-specific 15 alpha-hydroxylation and catechol formation.
The metabolism in the rat of 2,4-dibromo-17 beta-oestradiol (2,4-DBE2), a compound of potential use for tumour imaging and assessment, has been studied. 2,4-DB[6,7-3H]E2 was synthesized by bromination of [6,7-3H]E2 with N-bromosuccinimide, and administered (40 micrograms/kg, i.v.) to anaesthetized male and female rats. Metabolites were rapidly and extensively excreted in bile (60 and 82% of the dose over 1 and 6 h, respectively). No unchanged compound was excreted. 2,4-DBE2 was almost entirely oxidized to 2,4-DB-oestrone; which was largely eliminated as its glucuronide but partly (approx. 30%) metabolized to 2,4-DB-16 alpha-hhydroxyoesterone and, to a minor extent, 2,4-DB-oestriol. No products of either oxidative or reductive debromination were detected. Neither of the two oxidative transformations of 2,4-DBE2 in the rat, in contrast with those of exogenous E2, was sex-selective, and 2,4-DB-oestrone underwent less extensive hydroxylation than oestrone formed from E2. In female rats, the substituents selectively redirected the principal site of hydroxylation from C-2 to C-16, whereas in males they had no significant effect on the existing 16 alpha-hydroxylation but did block the major pathway, 15 alpha-hydroxylation. Thus the sexual differentiation of E2 oxidative metabolism was abolished by direct blockage causing metabolic switching to a latent reaction in the female rat and long-range inhibition of the vicinal hydroxylation in the male rat.
Maggs
J L
JL
Department of Pharmacology and Therapeutics, University of Liverpool, England.
Hussain
F
F
Page
P C
PC
Park
B K
BK
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001646:Bile / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002393:Estrogens, Catechol / Q000096:biosynthesis*; D004970:Estrone / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism*
D002393:Estrogens, Catechol; D005965:Glucuronates; C074040:2,4-dibromo-17-estradiol; D004970:Estrone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C050356:steroid 15-alpha-hydroxylase