2-methoxyestrone and 2-hydroxyestradiol

The effects of 2-hydroxy and 2-methoxy oestrogens on the extraneuronal O-methylation of 3H-(-)-noradrenaline were examined in progesterone-dominated, monoamine oxidase (MAO)-inhibited, rabbit uterine tissues in vitro. Both the corticosteroid-sensitive system in myometrium and the cocaine-sensitive system in endometrium were examined. In myometrial slices preincubated with nialamide to inhibit MAO and incubated with cocaine to inhibit neuronal uptake, 3H-normetanephrine (3H-NMN) formation was inhibited in the order of potency 2-hydroxy oestrone greater than or equal to 2-hydroxy oestradiol = 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone. In myometrial slices not exposed to cocaine and nialamide, inhibition of 3H-NMN formation by both 2-hydroxy and 2-methoxy oestradiol did not affect the formation of deaminated metabolites of 3H-(-)-noradrenaline by the alternative metabolising pathway. In endometrial slices preincubated with nialamide to inhibit MAO, only 2-hydroxy oestrogens inhibited 3H-NMN formation, but they were one to two orders of magnitude less potent in this regard than in the myometrium. The uptake of 3H-(-)-noradrenaline by MAO- and COMT-inhibited myometrial slices was inhibited by 2-hydroxy and 2-methoxy oestrogens in the order of potency 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone greater than or equal to 2-hydroxy oestrone greater than 2-hydroxy oestradiol. Uptake of 3H-(-)-noradrenaline by endometrial slices was not affected by either 2-hydroxy or 2-methoxy oestrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Methoxyestradiol; Animals; Catechol O-Methyltransferase Inhibitors; Endometrium; Estradiol; Estrogens, Catechol; Female; Hydroxyestrones; Methylation; Monoamine Oxidase Inhibitors; Myometrium; Norepinephrine; Rabbits; Tritium

Plasma levels of 2-hydroxyestradiol (2-OHE2) were measured using a new RIA procedure. Values were below the detection limit of the assay (less than 10 pg/ml), except in the third trimester of pregnancy, when they rose to approximately 15 pg/ml. The infusion of 130 microgram/h purified 2-OHE2 elevated its plasma concentration to 155 pg/ml, consistent with a plasma MCR (MCRp) of approximately 20,000 liters/day. The infusion of [3H] 2-OHE2 to equilibrium and chromatographic separation of the extracted plasma metabolites yielded an MCRp of about 13,000 liters/day; the major plasma metabolite comigrated with 2-methoxyestradiol, and [3H] xi-methoxyestrone was also formed. The MCRp, of 2-OHE2 is approximately half that of 2-hydroxyestrone (2-OHE1), but much higher than those of other steroids. As is true for 2-OHE1, the clearance of 2-OHE2 must occur primarily in the blood compartment. Together, the measured MCRp values and estrogen receptor affinities of 2-OHE2 and 2-OHE1 predict a relative potency for effects upon gonadotropin secretion which is close to that observed in vivo.

Topics: 2-Methoxyestradiol; Adult; Chromatography, Ion Exchange; Chromatography, Paper; Chromatography, Thin Layer; Estradiol; Female; Half-Life; Humans; Hydroxyestrones; Male; Metabolic Clearance Rate; Middle Aged; Radioimmunoassay

Topics: Animals; Catechols; Enzyme Induction; Estradiol; Estriol; Estrogens; Estrogens, Catechol; Female; Hydroxyestrones; Peroxidases; Rats; Structure-Activity Relationship; Uterus

Five catechol estrogens and two 2-methoxyestrogens were compared for their relative affinity of binding to hypothalamic, pituitary, and uterine cytosol estrogen receptors; and for the kinetics of the catechols' methylation by hepatic catechol-0-methyltransferase. All of the catechol estrogens tested have similar Km's for 0-methylation (9-14 muM). Estrogen receptor affinities, however, differ widely. In hypothalamus, for example, where estradiol-17 beta has a Kd of 0.039 +/- 0.008 nanomolar, 4-hydroxyestradiol also binds tightly (0.12 +/- 0.02 nM), 2-hydroxyestradiol and 4-hydroxyestrone with intermediate affinity (0.26 +/- 0.06 and 0.28 +/- 0.07 nM, respectively), and 2-hydroxyestrone and 2-hydroxyestriol much less well (1.68 +/- 0.79 and 1.27 +/- 0.26 nM, respectively). The binding of the 2-methoxyestrogens is extremely weak. These receptor affinities roughly parallel the potencies of these compounds in altering gonadotropin secretion.

Topics: 2-Methoxyestradiol; Animals; Binding Sites; Catechol O-Methyltransferase; Cytosol; Estradiol; Estriol; Female; Hydroxyestrones; Hypothalamus; Liver; Methylation; Pituitary Gland; Rats; Receptors, Estrogen; Substrate Specificity; Uterus

Topics: Biochemical Phenomena; Estradiol; Estrogens; Humans; Hydroxyestrones; Methylation