2-methoxyestrone and 2-hydroxyestrone

There are many kinds of estrogens, and endogenous estrogens produce a variety of estrogen metabolites with similar structure but with different physiological effects after metabolism in vivo. Studies have shown that estrone (E1) widely occurs in the environment and animal-derived food. Because of its estrogen effect, E1 can have adverse effects on the human body as an endocrine disruptor. In this study, we found that E1 and 2-hydroxyestrone (2-OH-E1), the hydroxylation metabolite of estrogen, have opposite proliferative effects on breast cancer cells (MCF-7) through cell proliferation experiments and comparison of their effects by molecular docking and detection of ROS, Ca

Topics: Cell Proliferation; Endocrine Disruptors; Estradiol; Estrogens; Estrone; Female; Humans; Hydroxyestrones; Hydroxylation; Inflammation; MCF-7 Cells; Molecular Docking Simulation; Oxidative Stress; Toxicity Tests

The main estradiol metabolites 2-hydroxyestrone, 2-methoxyestrone and 16alpha-hydroxyestrone were investigated in vitro for the susceptibility of low density lipoprotein to oxidation and the effects compared with those of estradiol and vitamin E. 2-hydroxyestrone and 2-methoxyestrone had a greater inhibitory effect than estradiol and vitamin E whereas 16alpha-hydroxyestrone approximates the inhibition of estradiol. These results indicate that 2-hydroxyestrone and 2-methoxyestrone possess non-genomic actions which may play a role in the lipid metabolism.

Topics: Estradiol; Estrogens, Catechol; Humans; Hydroxyestrones; Kinetics; Lipoproteins, LDL; Oxidation-Reduction; Vitamin E

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

To clarify the mechanism of action of catecholestrogen and catecholestrogen 2-monomethylether on lipid metabolism, the effects of 2-OHE1, 2-MeoE1, 2-MeoE3 and E2-17 beta on serum total cholesterol, HDL-cholesterol, triglyceride levels, beta/alpha lipoprotein ratio, body weights and uterine weights were investigated in five serial experimental systems using normochoesterolemic and dietary hypercholesterolemic female rats those were previously oophorectomized. The results obtained were as follows: 1) In a short term hormone administration experiment using normocholesterolemic rats, 2-OHE1, 2-MeoE1, and 2-MeoE3 showed a serum triglyceride reducing effect as strong as that of E2-17 beta. 2) To integrate the results of the short term hormone administration experiment in normocholesterolemic rats and the results of short term and long term hormone administration experiments in dietary hypercholesterolemic rats, the serum cholesterol reducing activity was in the following sequences; 2-MeoE3 not equal to E2-17 beta greater than 2-MeoE1 greater than 2-OHE1. Hypocholesterolemic activity of 2-MeoE3 was almost equivalent or slightly stronger than that of E2-17 beta, and 2-MeoE1 showed approximately a half of that of E2-17 beta. 3) According to the results of the short term hormone administration experiment, and the long term hormone administration experiment in dietary hypercholesterolemic rats, the serum HDL-cholesterol increasing effect was in the following relation; E2-17 beta greater than 2-MeoE3 greater than 2-MeoE1. Dose dependency was not observed in the serum HDL-cholesterol increasing effect. 4) From the results of the short term hormone administration experiment, 2-MeoE3 had an equal or stronger activity than that of E2-17 beta in serum beta/alpha lipoprotein ratio decreasing effect. 5) In experiment 4 which 2-MeoE3 and E2-17 beta were administered singly or combined with Tamoxifen to the dietary hypercholesterolemic rats, the hypocholesterolemic effect of neither hormone was inhibited by Tamoxifen. On the other hand, the uterotrophic activity of E2-17 beta was slightly, but not significantly inhibited by Tamoxifen. 6) Although E2-17 beta, 2-MeoE1 exhibited a remarkable uterotrophic activity and a slight reducing effect on body weight, neither 2-OHE1 nor 2-MeoE3 had an effect on uterine weight or body weight. Given these results, it was strongly suggested that the effects of catecholestrogen and catecholestrogen 2-monomethyl ether on serum lipids were not m

Topics: Animals; Cholesterol; Cholesterol, HDL; Diet; Estradiol; Estriol; Female; Hydroxyestrones; Hypercholesterolemia; Ovariectomy; Rats; Rats, Inbred Strains; Triglycerides

Studies of steroids and plasma lipoproteins in male cigarette smokers reveal that smoking is associated with an increase in peripheral estrogens and a decrease in high-density lipoprotein-cholesterol (HDL-C). We hypothesized that the lower HDL-C in this setting results in part from induction of the hepatic metabolic pathway that inactivates estrogen. This pathway, estradiol 2-hydroxylation, produces the peripherally inactive catechol estrogens 2-hydroxyesterone and 2-methoxyestrone. We used an in vivo radiometric method to assess 2-hydroxylation in 20 male smokers and 16 nonsmokers. The extent of the reaction (+/- SEM) was significantly higher among the smokers (43.3% +/- 1.9% v 24.6% +/- 1.9%, P less than .001). Smokers also excreted more urinary 2-hydroxyestrone (10.4 +/- 1.3 micrograms/g creatinine v 6.3 +/- 0.73 micrograms/g in nonsmokers, P = .011). The ratio of urinary 2-hydroxyestrone to estriol was higher on average among smokers (1.46 +/- 0.19 v 0.81 +/- 0.11, P = .006), and individual values correlated well with the radiometric test (r = .71, P less than .002). These data indicate that smoking is associated with significantly increased estrogen 2-hydroxylation in men. Preliminary evidence suggests that the smoking effect on C-2 hydroxylation may be opposed by ethanol. Elevated 2-hydroxylation in smokers, in the setting of modestly increased peripheral estrogens and a net decrease in HDLC, may be explained by the fact that lipoprotein synthesis and estrogen 2-hydroxylation both occur predominantly in the liver. Thus, greater metabolic inactivation of hepatic estrogens in male smokers could reduce HDLC, despite a modest rise in circulating hormone levels.

Topics: Adult; Arteriosclerosis; Estriol; Estrogens; Humans; Hydroxyestrones; Hydroxylation; Liver; Male; Middle Aged; Smoking

Epidemiologic data indicate that cigarette smoking is associated with an important anti-estrogenic effect, and increased hepatic metabolism has been suggested as a possible mechanism. We examined the hypothesis that cigarette smoking in women induces an increase in estradiol 2-hydroxylation. This irreversible metabolic pathway yields 2-hydroxyestrogens, which possess minimal peripheral estrogenic activity and are cleared rapidly from the circulation. We found a significant increase in estradiol 2-hydroxylation in premenopausal women who smoked at least 15 cigarettes per day. The extent of the reaction (mean +/- SEM) was 53.6 +/- 2.2 percent among 14 smokers and 35.1 +/- 1.8 percent among 13 nonsmoking controls--an increase of approximately 50 percent (P less than 0.001). The extent of 2-hydroxylation among five smokers did not vary during the follicular and luteal phases of their menstrual cycles. In addition, urinary excretion of estriol relative to estrone was significantly decreased among smokers (P less than 0.01), providing evidence that the smoking-induced increase in 2-hydroxylation diminishes the competing metabolic pathway involving 16 alpha-hydroxylation. This study demonstrates that smoking exerts a powerful inducing effect on the 2-hydroxylation pathway of estradiol metabolism, which is likely to lead to decreased bioavailability at estrogen target tissues. Elucidation of the mechanism responsible for smoking-induced changes in 2-hydroxylation may be useful in the development of strategies to reduce the risk of hormone-dependent tumors.

Topics: Adult; Estradiol; Estrogens; Female; Humans; Hydroxyestrones; Hydroxylation; Menopause; Menstrual Cycle; Smoking; Steroid 16-alpha-Hydroxylase

The plasma and tissue concentrations of 2-methoxyestrone (2-MeOE1) and 2-hydroxyestrone (2-OHE1) were measured in immature rats. The plasma levels of 2-MeOE1 were found to be high at birth and to decrease through puberty, when the low levels found in the adult rats were achieved. 2-OHE1 was undetectable in the plasma and brain, and barely detectable in the uterus and liver. 2-MeOE1 was undetectable in the brain and uterus, but high in the liver. The affinity of 2-MeOE1 and 2-OHE1 for rat alpha-fetoprotein was found to be low, while the affinity of estradiol, estrone, 4-hydroxyestrone, and 4-fluoroestradiol was high. This data suggests that 2-OHE1 and 2-MeOE1 would be available to estrogen target tissues in the fetal and neonatal rat. Although these metabolites lack uterotropic activity they are capable of acting in the liver. It is suggested that the plasma 2-MeOE1 of neonatal rats acts as a prohormone capable of stimulating the liver and other estrogen target tissues which possess demethylating enzymes. It is pointed out that unlike estradiol the non-steroidal estrogens such as diethylstibestrol (DES) lack the ability to form two sets of catechol and guaicol metabolites, i.e. "C-2" and "C-4" metabolites with their different biological characteristics are not formed by DES.

Topics: Aging; Animals; Animals, Newborn; Brain; Estrogens; Estrogens, Catechol; Estrone; Female; Hydroxyestrones; Liver; Male; Rats; Receptors, Estrogen; Structure-Activity Relationship; Tissue Distribution; Uterine Contraction; Uterus

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: Adult; Estrone; Glucuronates; Half-Life; Humans; Hydroxyestrones; Male; Metabolic Clearance Rate; Sulfates

The nonuterotropic metabolite of estradiol, 2-hydroxyestrone, administered at noon of proestrus to four-day cycling rats, abolishes the preovulatory prolactin rise in a large percentage of animals tested. In animals synchronized with exogenous estradiol, 2-hydroxyestrone universally induced a long delay in the prolactin surge. The principal metabolite of 2-hydroxyestrone, 2-methoxyestrone, given at noon of proestrus, significantly augments the magnitude of the preovulatory prolactin rise possibly by inhibiting the formation of endogenous 2-hydroxyestrogens in the brain. The results obtained are consistent with the concept of a physiological function for 2-hydroxyestrogens as estrogen antagonists in the CNS.

Topics: Animals; Estradiol; Estrone; Female; Hydroxyestrones; Ovulation; Pregnancy; Proestrus; Prolactin; Rats

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