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PubMed1980

Evidence of the directive effect of 17 beta-conjugate group on the enzymatic O-methylation of catechol estrogen.

Incubations of 2-hydroxyestradiol (I), 2-hydroxyestradiol 17 beta-sulfate (II), and 2-hydroxyestradiol 17 beta-glucuronide (III) with purified rat liver catechol O-methyltransferase were carried out at pH 7.2 in the presence of Mg2+ and (3H-Me)-S-adenosyl-L-methionine. The radioactive methylated products, 2-methoxyestradiol (IV) and 2-hydroxyestradiol-3-methyl ether (V), from each substrate were quantificanted by reverse isotope dilution method after their complete separation and acetylation. In the experiments of conjugated substrates, II and III, the analyses of the methylated products were done after their hydrolysis of 17 beta-conjugate groups with acid or beta-glucuronidase. The product ratios (2-methoxy/3-methoxy) of substrates I, II, and III, were 1:1, 4:1, and 45:1, respectively. These results are suggesting that 17 beta-conjugate groups of 2-hydroxyestradiol has directive effect on enzymatic O-methylation of estrogen catechols. Further, it is estimated that following process may be present in the estradiol metabolism in rat and/or humans: estradiol leads to estradiol 17 beta-conjugates leads to 2-hydroxyestradiol 17 beta-conjugates leads to 2-methoxyestradiol 17 beta-conjugates.

Animals↗

PubMed1983

Regulation of cytochrome P-450-dependent catechol estrogen formation in rat liver microsomes. Evidence for involvement of estrogen receptors.

Experiments were conducted to evaluate whether estrogen 2-hydroxylase activity in liver microsomes, the main pathway for oxidative metabolism of estrogens in the rat, is regulated by administration of synthetic estrogens. Ovariectomized rats were treated with ethinylestradiol (EE), 100 micrograms s.c. for 3 days. Liver microsomes from EE-treated animals showed a 2-fold increase over control in estrogen 2-hydroxylase activity measured over a substrate concentration range of 0.5 to 50 microM. Double-reciprocal plots of enzyme activity as a function of substrate concentration were linear; apparent Vmax values were 2-fold greater in microsomes from EE-treated animals while apparent Km values for control and EE preparations were not different. Administration of the triphenylethylene antiestrogen tamoxifen (TAM), 100 micrograms s.c. for 3 days, did not affect microsomal catechol estrogen formation activity, and apparent Km and Vmax values were comparable with controls. When EE and TAM were co-administered, no increase in microsomal estrogen 2-hydroxylase was observed, and apparent Km and Vmax values were not different from either control of TAM-treated preparations. Thus, acute administration of EE was associated with a specific increase in the apparent Vmax of estrogen 2-OHase activity, and this effect was not observed when TAM was co-administered with the estrogen.

Animals↗

PubMed1984

Effects of catechol estrogen methyl ethers on lipid metabolism in prepubertal rats.

Thirty-five day old ovariectomised rats were given daily subcutaneous injections (0.05-5.0 micrograms/100 gm body weight) of estradiol (E2) 2-methoxyestradiol (2-ME2) or 4-methoxyestradiol (4-ME2) for six days. At the end of the last injection, the animals were sacrificed and serum lipoproteins were analysed. It was observed that cholesterol decreased significantly in normal fed animals who received E2 and 4-ME2, while no effect was seen in cholesterol fed animals. In the E2 treated group there was a decrease in esterified and free cholesterol, while in the 4-ME2 group only esterified cholesterol decreased. High density lipoproteins were significantly elevated in the E2 treated group. However, there was an increase in very low density lipoproteins and a decrease in low density lipoproteins in 2-ME2 and 4-ME2 treated groups. These results suggest that catechol estrogens may play an important role in the lipoprotein metabolism and atherosclerotic diseases, and the mechanism of action may differ from that of estradiol.

2-Methoxyestradiol↗

PubMed1987

Modulation of catechol estrogen synthesis by rat liver microsomes: effects of treatment with growth hormone or testosterone.

The ability of GH from various mammalian species, administered to normal mature male rats by constant infusion, to decrease the hepatic 2-hydroxylation of estradiol (E2) to female levels, as measured by the release of 3H2O from [2-3H]E2, was determined. Rat and human GH (hGH) showed the highest activity while ovine GH was inactive. PRL (0.6 IU/h X kg) administered together with hGH (0.02 IU/h X kg) did not antagonize the feminizing action of GH. Infusion of hGH into male rats decreased the affinity of estradiol 2-hydroxylase for its steroid substrate and altered the linear Lineweaver-Burk plot towards a nonlinear hyperbolic plot characteristic of the female. The apparent Michaelis-Menten constant (Km) for the reaction was 1.69 microM for males and 2.75 microM for testosterone-treated ovariectomized females. An equal mixture of liver microsomes from male and female rats gave kinetic values similar to those observed with males alone. Neonatal imprinting with androgen did not alter the magnitude of the response of female rats to treatment with testosterone and/or GH at maturity and the androgen effect could only be shown in ovariectomized animals. The results with rats of different endocrine status were corroborated by the kinetic data and by the pattern of metabolites obtained with [4-14C]E2 when examined by TLC and autoradiography. The hormonal control of estradiol 2-hydroxylase, the key enzyme in catechol estrogen formation, and the contribution of sex-specific multiple forms of the enzyme to this reaction are discussed.

Animals↗

PubMed1990

Cloning and expression of human liver UDP-glucuronosyltransferase in COS-1 cells. 3,4-catechol estrogens and estriol as primary substrates.

The human cDNA clone, UDPGTh-2, encoding a liver UDP-glucuronosyltransferase (transferase) was isolated from a lambda gt11 cDNA library by hybridization to the mouse transferase cDNA clone, UDPGTm-1 (Kimura, T., and Owens, I. S. (1987) Eur. J. Biochem.168, 515-521). The two clones have nucleotide sequence identities in the coding region of 74%. UDPGTh-2 encodes a 529-amino acid protein with an NH2 terminus membrane-insertion signal peptide and a carboxyl terminus membrane-spanning region. There are three potential asparagine-linked glycosylation sites at residues 67, 68, and 315. In order to establish substrate specificity, the clone was inserted into the pSVL vector (pUDPGTh-2) and expressed in COS-1 cells. The presence of a transferase with Mr congruent to 52,000 in transfected cells cultured in the presence of [35S]methionine was shown by immunocomplexed products with goat antimouse transferase IgG (Mackenzie, P. I., Hjelmeland, L. H., and Owens, I. S. (1984) Arch. Biochem. Biophys. 231, 487-497) and protein A-Sepharose and analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. The transferase is a glycoprotein as indicated by a shift in Mr congruent to 3000-4000 when expressed in the presence of tunicamycin. Sixty potential substrates were tested using cells transfected with pUDPGTh-2. The order of relative substrate activity was as follows: 4-hydroxyestrone greater than estriol greater than 2-hydroxyestriol greater than 4-hydroxyestradiol greater than 6 alpha-hydroxyestriol greater than 5 alpha-androstane-3 alpha,11 beta,17 beta-triol = 5 beta-androstane-3 alpha,11 beta,17 beta-triol. There were only trace amounts of glucuronidation of 2-hydroxyestrone and 2-hydroxyestradiol, and, in contrast to other cloned transferases, no glucuronidation of either the primary estrogens/androgens (estrone, 17 beta-estradiol/testosterone, androsterone) or any of the exogenous substrates tested. A Lineweaver-Burk plot of the effect of 4-hydroxyestrone concentration on the velocity of glucuronidation shows an apparent Km of 13 microM. The unique specificity of this transferase for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites.

Amino Acid Sequence↗

PubMed1986

Effect of catechol estrogens on the preovulatory content of luteinizing hormone-releasing hormone in the median eminence of the rat.

Cycling rats injected with 2-hydroxyestrone or 2-hydroxyestradiol at 09.00 or 10.00 h in the morning of proestrus do not express the normal preovulatory LH surge in the afternoon of the day. The LHRH content of the median eminence in control animals decreases sharply in the afternoon from elevated noon and morning levels. The catechol estrogen-treated rats fail to show the decrease. Thus the catechol estrogens block the LH surge at its usual time by influencing the changes in the concentration of LHRH in the median eminence on proestrus. Since the catechol estrogens have short biological half-lives, their effect on the LHRH content in the afternoon must originate in the morning at the time of the endogenous estradiol (E2) peak. These results have implications in the physiological processes responsible for the positive feedback of estradiol on the preovulatory LH surge in the rat.

Animals↗

PubMed1977

Metabolism of catechol estrogen by human erythrocytes.

In a study designed to evaluate the kinetics of catechol estrogen formation from plasma estrone in vivo, we obtained evidence that the red blood cell (RBC) enzyme, catechol-O-methyl transferase, catalyzes the transformation of 2-hydroxyestrone to 2-methoxyestrone. Under in vitro conditions, the rate of conversion of 2-hydroxyestrone to 2-methoxyestrone by human RBC's was such that 7 nmol of 2-methoxyestrone were formed per h per ml of RBC.

Catechol O-Methyltransferase↗

PubMed2002

Adduction of catechol estrogens to nucleosides.

We report the formation, detection, quantitation and structural characterization of products resulting from the adduction of deoxynucleosides (deoxyadenosine, deoxyguanosine, deoxycytidine and 5-methyldeoxycytidine) to the catechol estrogens (CE) of estrone, estradiol-17beta and estradiol-17 alpha. The crude products are obtained in a one-pot synthesis through oxidation of catechols to quinones and subsequent Michael-type reaction with the deoxynucleosides in acidic medium. In all experiments, adducts are detected by electrospray ionization mass spectrometry analysis after HPLC separation (LC/ESI/MS(n)). The two pyrimidines deoxycytidine and 5-methyldeoxycytidine yield only CE adducts to deoxynucleosides, which correspond to stable adducts on DNA. For purines, the results depend on the CE (2,3- or 3,4-catechols) used, the function and configuration on carbon 17 (ketone for estrone, alcohol for alpha and beta isomers of estradiol), and on the purine itself (deoxyadenosine or deoxyguanosine). Both stable adducts and deglycosylated adducts are formed, and therefore formation of stable adducts on DNA as well as the loss of purines from the DNA strands could be possible. MS(2) and MS(3) experiments prove to be relevant for further structural determinations, enabling in some cases the elucidation of the regiochemistry of adduction on the A and B rings of the steroid moiety.

Chromatography, High Pressure Liquid↗

PubMed2005

Risk of testicular germ cell cancer in relation to variation in maternal and offspring cytochrome p450 genes involved in catechol estrogen metabolism.

The incidence of testicular germ cell carcinoma (TGCC) is highest among men ages 20 to 44 years. Exposure to relatively high circulating maternal estrogen levels during pregnancy has long been suspected as being a risk factor for TGCC. Catechol (hydroxylated) estrogens have carcinogenic potential, thought to arise from reactive catechol intermediates with enhanced capability of forming mutation-inducing DNA adducts. Polymorphisms in maternal or offspring genes encoding estrogen-metabolizing enzymes may influence prenatal catechol estrogen levels and could therefore be biomarkers of TGCC risk. We conducted a population-based, case-parent triad study to evaluate TGCC risk in relation to maternal and/or offspring polymorphisms in CYP1A2, CYP1B1, CYP3A4, and CYP3A5. We identified 18- to 44-year-old men diagnosed with invasive TGCC from 1999 to 2004 through a population-based cancer registry in Washington State and recruited cases and their parents (110 case-parent triads, 50 case-parent dyads). Maternal or offspring carriage of CYP1A2 -163A was associated with reduced risk of TGCC [maternal heterozygote relative risk (RR), 0.6; 95% confidence interval (95% CI), 0.2-1.7; offspring heterozygote RR, 0.7; 95% CI, 0.3-1.5)]. Maternal CYP1B1 (48)Gly homozygosity was associated with a 2.7-fold increased risk of TGCC (95% CI, 0.9-7.9), with little evidence that Leu(432)Val or Asn(453)Ser genotypes were related to risk. Men were also at increased risk of TGCC if they carried the CYP3A4 -392G (RR, 7.0; 95% CI, 1.6-31) or CYP3A5 6986G (RR, 2.4; 95% CI, 1.1-5.6) alleles. These results support the hypothesis that maternal and/or offspring catechol estrogen activity may influence sons' risk of TGCC.

Adolescent↗

PubMed1993

Microsomal hydroxylation of 2- and 4-fluoroestradiol to catechol metabolites and their conversion to methyl ethers: catechol estrogens as possible mediators of hormonal carcinogenesis.

In male Syrian hamsters, an animal model for estradiol-induced carcinogenesis, 2-fluoroestradiol was not carcinogenic, whereas 4-fluoroestradiol induced kidney tumors after a prolonged latency period, compared with estradiol (100% tumor incidence), when the compounds were administered to hamsters in hormonally equipotent doses. Catechol estrogen metabolites have previously been postulated to mediate this estrogen-induced kidney carcinogenesis. To examine this proposed mechanism of tumor induction by estrogens, we investigated the conversion of 2- and 4-fluoroestradiol to catechol metabolites by kidney and liver microsomes of hamsters and the further conversion to methyl ethers by catechol-O-methyltransferase, and we compared the values with those obtained with nonfluorinated estrogens as substrates. The rates of conversion of 2-fluoroestradiol to 2-hydroxyestradiol and 2-fluoro-4-hydroxyestradiol by hepatic microsomes were 30-50% lower than corresponding rates with estradiol as substrate. With renal microsomes the rate of 4-hydroxylation was 10 times faster than that of estradiol, whereas 2-hydroxylation was at best marginal. With 4-fluoroestradiol as substrate the rate of 2-hydroxylation by hepatic microsomes was enhanced 5-fold, compared with values for estradiol, but 4-hydroxyestradiol formation was almost eliminated. In contrast, the conversion of this substrate to 4-fluoro-2-hydroxyestradiol by kidney microsomes occurred at a rate 15 times faster than 2-hydroxylation of estradiol, whereas 4-hydroxyestradiol formation proceeded at a rate of 315 pmol/mg of protein/min. Except for the decrease in both 2- and 4-hydroxylation of 2-fluoroestradiol by liver microsomes, fluorine substitution of estrogenic phenols enhanced microsome-mediated aromatic hydroxylation at sites unoccupied by substituents. At pH 7.5, the highest rates of catechol-O-methyltransferase-mediated methylation were observed with the catechol metabolites of 2-fluoroestradiol, 2-fluoro-4-hydroxyestradiol and 2-hydroxyestradiol (3780 and 2960 pmol/mg of protein/min, respectively). Lower rates were found with those of 4-fluoroestradiol, 4-fluoro-2-hydroxyestradiol and 4-hydroxyestradiol (1670 and 470 pmol/mg of protein/min, respectively). These data are consistent with the postulate that catechol metabolites of estrogens are reactive intermediates in estrogen-induced carcinogenesis. For the noncarcinogenic 2-fluoroestradiol, a high metabolic flux was observed through a pathway of renal 2-fluoro-4-hydroxyestradiol formation and further conversion to methyl ethers. This flux likely results in low steady state concentrations of catechol metabolites in kidneys of hamsters treated with this modified estrogen and therefore in its lack of carcinogenic activity. In contrast, the carcinogenic activity of 4-fluoroestradiol is consistent with its rapid conversion in the kidney to 2- and 4-hydroxylated metabolites and a less rapid methylation of these catechols.

Animals↗

PubMed1975

Catechol estrogen formation in the central nervous system of the rat.

Conversion of estradiol and estrone to catechol estrogens by rat hypothalamic tissue but not by the cerebral cortex was demonstrated from the incubation of these tissues with estradiol-2-3H and estrone-2-3H and monitoring the incorporation of tritium into water. Direct evidence for this transformation was obtained by isolating the labelled phenazine derivative of 2-hydroxyestrone after hypothalamic incubation with estrone-4-14C.

Animals↗

PubMed1979

Impact of continuously administered catechol estrogens on uterine growth and luteinizing hormone secretion.

The biological activity of a series of natural catechol estrogens was examined under conditions of continuous administration. 2-Hydroxyestradiol (2OH-E2), 2-methoxyestradiol (2MeOE2), 4-hydroxyestrone (4OH-E1), 4-methoxyestradiol (4MeOE2), 2-hydroxyestrone (2OH-E1), and 4-methoxyestrone (4MeOE1) were delivered at the rate of 1 microgram/h from osmotic pumps implanted in ovariectomized rats. Uterine growth and plasma LH concentrations were measured 24, 48, and 72 h after implantation. Little or no uterotropic activity was exhibited by the 2-hydroxylated metabolites 2OH-E1 and 2MeOE2 at any interval, while 2OH-E2 exhibited anomalous uterotropic activity, which terminated at 48 h. The 4-hydroxylated compounds 4MeOE2, 4OH-E1, and 4MeOE1 all produced substantial and progressive uterine growth. Tonic LH secretion was suppressed by 2OH-E2, 4OH-E1, and 4MeOE1 in proportion to their uterotropic activity. 2OH-E1 was the only substance which increased plasma LH concentrations. The nuclear receptor occupancy by 2OH-E2 was substantially shorter than that of E2. Binding studies of the test and other related estrogens to the uterine cytosol estradiol receptor showed that their relative binding affinities in many instances did not correlate with their biological activities.

Animals↗

PubMed1987

[Mechanism of the suppressive effect of catechol estrogen on the preovulatory LH surge].

The administration of 100 micrograms 2-hydroxyestrone (2-OHE1) or 2-hydroxyestradiol-17 beta (2-OHE2) at 0900h or 1000h in the morning of proestrus into normal 4-day cycling rats results in suppression of the preovulatory LH surge in the afternoon of that day. The LH-RH content of the median eminence in control rats decreases sharply in the afternoon from elevated noon levels. However, the catechol estrogen-treated rats do not show this decrease. These results indicate that the catecholestrogens block the preovulatory LH surge by preventing the release of LH-RH from the median eminence, but do not interfere with the synthesis and accumulation of LH-RH. Furthermore, injections of non-uterotropic 2-OHE1 twice at 30 minutes intervals into ovariectomized rats fail to affect the LH tonic secretion by 180 minutes after the initial injection. These data indicate that catechol estrogen interferes with the brief neuronal triggering phase necessary for LH-RH release, but does not affect the LH tonic secretion which is an estrogen-independent process.

Animals↗

PubMed1980

2-hydroxyestradiol-17 alpha and 4-hydroxyestradiol-17 alpha, catechol estrogen analogs with reduced estrogen receptor affinity.

2-Hydroxyest radiol-17 alpha and 4-hydroxyestradiol-17 alpha, the catechol derivatives of estradiol-17 alpha, have reduced affinity for hypothalamic, pituitary, and uterine estrogen receptors, but retain a potency for interaction with catechol-0-methyltransferase equal to that of the natural, 17 beta-hydroxy catechols. This dissociation of receptor binding and catecholamine interactions may allow the use of the 17 alpha catechols as a probe for the mechanism of action of the catechol estrogens.

Amygdala↗

PubMed2000

Studies on neurosteroids XII. Determination of enzymatically formed catechol estrogens and guaiacol estrogens by rat brains using liquid chromatography-mass spectrometry-mass spectrometry.

Enzymic formations of catechol- and guaiacol-estrogens by rat brains have been investigated using classical- and catechol-estrogens as substrates, respectively. The incubation mixtures were pretreated with liquid-liquid and/or solid-phase extraction, and the products were identified by comparison with authentic samples using liquid chromatography-mass spectrometry (-mass spectrometry) [LC-MS (-MS)]. The enzymic activities were also determined by measuring the formed products with LC-MS.

Animals↗

PubMed1975

The affinity of catechol estrogens for estrogen receptors in the pituitary and anterior hypothalamus of the rat.

The purpose of these experiments was to evaluate the potential for interaction between 2-hydroxyestrone and 2-hydroxyestradiol and estrogen receptors in rat pituitary and anterior hypothalamus. The 150,000 X g supernatant fractions of these tissues were prepared, the estrogen receptor-site concentration was measured, and the relative abilities of unlabelled estradiol, estrone, 2-hydroxyestradiol and 2-hydroxyestrone to compete with [3H]estradiol for estrogen binding sites was determined. From these results, and the previously determined association constant for [3H]estradiol, 10(10)M-1, the association constants of the other estrogens were calculated. The introduction of the 2-hydroxy group caused only a modest reduction in the affinity of these estrogens for the receptors. The association constants of the 2-hydroxy derivatives were within one order of magnitude of those of the parent compounds. These results demonstrate the potential for interaction between catechol estrogens and estrogen receptor in rat brain and pituitary of a magnitude which could be biologically significant.

Animals↗

PubMed1990

Catechol estrogen formation in the mouse uterus and its role in implantation.

Estradiol-2/4-hydroxylase (E-2/4-H) activity was determined in the mouse uterus during early pregnancy as well as in ovarian steroid hormone-treated ovariectomized uterus. Under the assay conditions used, E-4-H was the predominant catechol estrogen-forming monooxygenase enzyme. The inhibition of E-4-H activity by SKF-525A, metyrapone and alpha-naphthoflavone suggested involvement of cytochrome P450-dependent monooxygenases. A haloestrogen, 2-fluoroestradiol (2-FL-E2), also inhibited this activity. During the peri-implantation period, no change in uterine E-4-H activity was noted on the morning of days 2 through 5, but the activity significantly (P less than 0.01) increased in the afternoon of day 4 of pregnancy. A single injection of estradiol-17 beta (E2, 100 ng/mouse) to ovariectomized mice significantly (P less than 0.01) elevated the level of E-4-H activity at 24 h as did injections of progesterone (P4, 2 mg/mouse) for 2 days. When 2 days of P4 (2 mg/mouse) treatment was combined with a single injection of E2 (20 ng/mouse), E-4-H activity increased 1.3-fold (P less than 0.05) by 24 h above that of P4 treatment alone. Dexamethasone (200 micrograms/mouse) and cholesterol (2 mg/mouse) treatment for 2 days had no effect on E-4-H activity. Thus, the stimulatory effect of P4 and E2 on E-4-H activity appeared to be specific. The increased activity of uterine E-4-H prior to implantation on day 4 evening and the modulation of its activity by P4 and/or E2 suggest an involvement of 4-hydroxyestradiol in embryo implantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Catechol estrogen formation in mouse uterus.

Estrogen 2/4-hydroxylase (ESH) and catechol-O-methyltransferase (COMT) activities in mouse liver and uterus were studied. While 2-hydroxyestradiol (2-OHE2) was the predominant product in the liver, equal amounts of 2- and 4-hydroxyestradiol were produced in the uterus. Two-hydroxyestradiol was the preferred substrate for COMT in both tissues, but the level of this enzyme activity was much less in the mouse uterus (17-fold less). Thus, preferential production of 4-hydroxyestradiol (4-OHE2) in the presence of relatively less deactivation provides a mechanism for the local formation of a more chemically active form of estrogen by uterine tissue.

Animals↗