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At least 19 recordsLinked to original sources
PubMed1998

Differential spatiotemporal regulation of lactoferrin and progesterone receptor genes in the mouse uterus by primary estrogen, catechol estrogen, and xenoestrogen.

Many xenobiotics are considered reproductive toxins because of their ability to interact with the nuclear estrogen receptors (ERalpha and ERbeta). However, there is evidence that these xenobiotics can regulate gene expression in the reproductive targets by mechanisms that do not involve these ERs. To examine this further, we compared the effects of estrogenic (o,p'-DDT [1-(o-chlorophenyl)-1-(p-chlorophenyl)2,2,2-trichloroethane] and Kepone, chlordecone) and nonestrogenic (p,p'-DDD [1,1-dichloro-2,2-bis(p-chlorophenyl)ethane], a metabolite of p,p'-DDT) xenobiotics with those of 17beta-estradiol (E2) and 4-hydroxyestradiol-17beta (4-OH-E2), a catechol metabolite of E2, on uterine expression of lactoferrin (LF) and progesterone receptor (PR). These genes are estrogen responsive in the mouse uterus. Normally, LF is expressed in the uterine epithelium, whereas PR is expressed in both the epithelium and stroma in response to estrogenic stimulation. Ovariectomized mice were injected with xenobiotics (7.5 mg/kg), E2 (10 microg/kg), 4-OH-E2 (10 microg/kg), or the vehicle (oil, 0.1 ml/mouse), and uterine tissues were processed for Northern blot and in situ hybridization. The pure antiestrogen ICI-182780 (ICI; 1 or 20 mg/kg) was used to interfere with estrogenic responses that were associated with the ERs. The results of Northern and in situ hybridization demonstrated increased uterine levels of PR and LF messenger RNAs (mRNAs) by all of these xenobiotics, but quantitatively the responses were much lower than those induced by E2 or 4-OH-E2. The results further showed that the E2-inducible epithelial LF mRNA accumulation was markedly abrogated by pretreatment with ICI (20 mg/kg). In contrast, this treatment retained the epithelial expression of PR mRNA, but down-regulated the stromal expression. In contrast, ICI had negligible effects on LF and PR mRNA responses to 4-OH-E2, indicating that this catechol estrogen exerted its effects primarily via a mechanism(s) other than the ERs. The heightened accumulation of LF mRNA in the epithelium in response to Kepone and o,p'-DDT was also severely compromised by pretreatment with ICI, but this antiestrogen had little effect on responses to p,p'-DDD. Similar to E2, Kepone increased the expression of PR mRNA in both uterine epithelium and stroma. However, pretreatment with ICI decreased stromal cell expression, whereas epithelial cell expression remained unaltered or increased. These responses were not noted in mice treated with o,p'-DDT or p,p'-DDD. Collectively, the results demonstrate that catechol estrogens or xenobiotics can alter uterine expression of estrogen-responsive genes by mechanisms that are not totally mediated by the classical nuclear ERs, and these alterations are cell type specific. We conclude that an interaction of a compound with the nuclear ERalpha and/or ERbeta is not an absolute requirement for producing specific estrogen-like effects in the reproductive target tissues.

Animals↗
PubMed2005

A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen.

Catechol estrogens are steroid metabolites that elicit physiological responses through binding to a variety of cellular targets. We show here that catechol estrogens directly inhibit soluble adenylyl cyclases and the abundant trans-membrane adenylyl cyclases. Catechol estrogen inhibition is non-competitive with respect to the substrate ATP, and we solved the crystal structure of a catechol estrogen bound to a soluble adenylyl cyclase from Spirulina platensis in complex with a substrate analog. The catechol estrogen is bound to a newly identified, conserved hydrophobic patch near the active center but distinct from the ATP-binding cleft. Inhibitor binding leads to a chelating interaction between the catechol estrogen hydroxyl groups and the catalytic magnesium ion, distorting the active site and trapping the enzyme substrate complex in a non-productive conformation. This novel inhibition mechanism likely applies to other adenylyl cyclase inhibitors, and the identified ligand-binding site has important implications for the development of specific adenylyl cyclase inhibitors.

Adenosine Triphosphate↗
PubMed1983

Inhibition of dihydropteridine reductase by catechol estrogens.

Catechol estrogens, such as 2-hydroxyestriol, 2-hydroxyestradiol, and 2-hydroxyestrone, inhibit human liver dihydropteridine reductase noncompetitively with Ki values ranging from 1.5 to 4.6 X 10(-6)M. Catechol estrogens lose approximately half of their inhibitory potency if the C-2 hydroxyl groups are methylated. Thus, 2-methoxyestrogens have inhibitory potencies equivalent to those of their parent estrogens--estriol, estradiol, and estrone. Aromatization of ring B or stereoisomerism at C-17 does not affect the inhibitory potency of estrogens, although stereoisomerism at C-16 enhances the inhibitory potency of estriol. These results support the hypothesis that catechol estrogens may interfere with catecholamine metabolism by acting as inhibitors of enzymes involved in catecholamine metabolism, such as dihydropteridine reductase.

Dihydropteridine Reductase↗
PubMed2000

Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens.

Catechol estrogens may mediate estrogen-induced carcinogenesis because 4-hydroxyestradiol induces DNA damage and renal tumors in hamsters, and this metabolite is formed in the kidney and estrogen target tissues by a specific estrogen 4-hydroxylase. We examined the carcinogenic potential of catechol estrogen in an experimental model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal exposure to diethylstilbestrol. Outbred female CD-1 mice were treated with 2- or 4-hydroxyestradiol, 17beta-estradiol, or 17alpha-ethinyl estradiol on days 1-5 of neonatal life (2 microg/pup/day) and sacrificed at 12 or 18 months of age. Mice treated with 17beta-estradiol or 17a-ethinyl estradiol had a total uterine tumor incidence of 7% or 43%, respectively. 2-Hydroxyestradiol induced tumors in 12% of the mice, but 4-hydroxyestradiol was the most carcinogenic estrogen, with a 66% incidence of uterine adenocarcinoma. Both 2- and 4-hydroxylated catechols were estrogenic and increased uterine wet weights in these neonates. These data demonstrate that both 2- and 4-hydroxyestradiol are carcinogenic metabolites. The high tumor incidence induced by 4-hydroxyestradiol supports the postulated role of this metabolite in hormone-associated cancers.

Adenocarcinoma↗
PubMed1978

Direct inhibition of tyrosine hydroxylase activity by catechol estrogens.

Catechol estrogens, the 2-hydroxylated metabolites of estrogens, recently shown to be formed in brain, inhibit tyrosine hydroxylase, the enzyme that catalyzes the pivotal step in the biosynthesis of the neurotransmitters dopamine and norepinephrine. The nature of the inhibition is by competition with the pterin cofactor and thus resembles feedback inhibition of the enzyme by catecholamines.

Animals↗
PubMed1986

Active nonaromatic intermediates in the conversion of steroidal estrogens into catechol estrogens.

A mechanism is proposed for mixed-function oxidase-catalyzed formation of the catechol estrogens 2-hydroxy- and 4-hydroxyestradiol from estradiol. This mechanism involves nonaromatic epoxyenones as intermediates. The isomeric 1 alpha,2 alpha-epoxy-17 beta-hydroxyestr-4-en-3-one and 1 beta,2 beta-epoxy-17 beta-hydroxyestr-4-en-3-one (the latter as its 17-acetate) were synthesized from 17 beta-hydroxy-5 alpha-estran-3-one. The isomeric 4 alpha,5 alpha-epoxy-17 beta-hydroxyestr-1-en-3-one and 4 beta,5 beta-epoxy-17 beta-hydroxyestr-1-en-3-one were prepared from 19-nortestosterone. From incubations of [6,7-3H]estradiol with microsomes from MCF-7 human breast cancer cells, which principally catalyze the formation of 2-hydroxyestradiol from estradiol, we were able to isolate a 3H-labeled product with the chromatographic properties of 1 beta, 2 beta-epoxy-17 beta-hydroxyestr-4-en-3-one (as its 17-acetate). The soluble protein fraction of homogenates of rat liver, which is devoid of estrogen 2-/4-hydroxylase activity, has been shown to catalyze the formation of 2- and 4-hydroxyestradiol from the 1 alpha,2 alpha-epoxide and from the 4 alpha,5 alpha- and 4 beta,5 beta-epoxides, respectively. We suggest that these results taken together strongly support a role for epoxyenones as intermediates in the formation of catechol estrogens.

Estrogens↗
PubMed1986

Effect of continuous intraventricular estrogen or catechol estrogen treatment on catecholamine turnover in various brain regions.

The effect of 7-day i.v.t. administration of catechol estrogens (CE) or estrogens (5 micrograms/day) on the catecholamine turnover rate of various brain areas was examined in ovariectomized rats. Norepinephrine turnover was increased significantly in the hypothalamus and cerebral cortex by estradiol treatment but not by any CEs tested when compared to control values. However, the turnover rate of dopamine in the cerebral cortex was increased compared to control values only by the 2-hydroxyestrogens (2-hydroxyestradiol and 2-hydroxyestrone) and estradiol was without effect. Only estrogens and CEs with physiologically significant estrogen receptor binding affinities (17 beta-estradiol, moxestrol, 2-hydroxyestradiol and 4-hydroxyestradiol) decreased the turnover rate of dopamine in the corpus striatum compared to control values. Estrogens (17 alpha-estradiol and 2-hydroxyestrone) which are weak ligands for the estrogen receptor did not affect striatal dopamine turnover. In addition, body weight gain measured during estrogen treatment was reduced by CEs and estrogens which have significant estrogen receptor affinities. These results suggest that the CEs may play a role in central modulation of catecholaminergic function by estrogens either through direct actions of the catechol moiety or activation of estrogen receptors.

Animals↗
PubMed1996

17 beta-estradiol metabolism by hamster hepatic microsomes: comparison of catechol estrogen O-methylation with catechol estrogen oxidation and glutathione conjugation.

Catechol estrogens, the cytochromes P450 mediated metabolites of 17 beta-estradiol, undergo further metabolism either via catechol O-methyltransferase (COMT) catalyzed methylation, or by oxidation and subsequent thioether formation with glutathione (GSH). Secondary metabolites of 17 beta-estradiol arising from both these metabolic pathways have been identified in vivo. However, the relative contribution of catechol O-methylation, and catechol oxidation followed by GSH conjugation, to the disposition of the catechol estrogens is unclear. We have therefore quantified both pathways of catechol estrogen disposition, generated in situ from 17 beta-estradiol, in hamster hepatic microsomes. 17 beta-Estradiol was readily converted to 2- and 4-hydroxy-17 beta-estradiol, both of which were effectively methylated in the presence of COMT (300 units/mL). Addition of GSH (50 microM-1 mM) to microsomal incubations resulted in the formation of four catechol estrogen-derived GSH conjugates. Three conjugates of 2-hydroxy-17 beta-estradiol were identified: 2-hydroxy-1,4-bis(glutathione-S-yl)-17 beta-estradiol, 2-hydroxy-1-glutathione-S-yl-17 beta-estradiol, and 2-hydroxy-4-glutathione-S-yl-27 beta-estradiol. In contrast, just one GSH conjugate of 4-hydroxy-17 beta-estradiol was identified: 4-hydroxy-1-glutathione-S-yl-17 beta-estradiol. When a combination of COMT and GSH were simultaneously added to microsomal incubations, both metabolic pathways competed for the same pool of catechol estrogens, and ascorbate dramatically influenced which of these two pathways predominate. In the presence of ascorbate, catechol estrogen methylation predominated over catechol estrogen oxidation and GSH conjugation. In the absence of ascorbic acid, catechol estrogen methylation, and catechol estrogen oxidation inked to GSH conjugation, contributed equally to the disposition of the catechol estrogens. 17 beta-Estradiol 2- and 4-hydroxylase activity was always higher in the absence of ascorbate, irrespective of whether GSH or COMT was used as the trapping agent. Thus, the usual method (COMT plus ascorbate) of determining 17 beta-estradiol 2- and 4-hydroxylase activity underestimates enzyme activity by approximately 50% when compared to the value obtained when GSH is used to trap the o-quinones in the absence of ascorbate. A reassessment of 17 beta-estradiol 2- and 4-hydroxylase activity in different species and tissues is required to permit a more informed evaluation of the role of catechol estrogens in estrogen-induced carcinogenesis.

Animals↗
PubMed1990

Inhibition of the soluble form of testis adenylate cyclase by catechol estrogens and other catechols.

The soluble form of rat germ cell adenylate cyclase was inhibited by compounds with a catechol moiety. Among the naturally occurring catechols tested, catechol estrogens were the most potent inhibitors. Catechol estrogens at 2-6 microM inhibited enzyme activity by 50% and almost completely at 30-100 microM concentration. The inhibitory activity of catechol estrogens depends on the catechol moiety of the molecule. Catechol per se also inhibited the activity of this enzyme, 50% inhibition being achieved at about 11 microM. The two hydroxyls of the catechol moiety are essential for the inhibitory interaction with the enzyme. Thus, aromatic compounds containing only one hydroxyl group in the benzene ring, such as tyrosine, phenylephrine, estradiol, and 6 alpha-hydroxyestradiol were either completely inactive or had marginal inhibitory activity at concentrations up to 0.3-1 mM. Moreover, methylation of the hydroxyl groups of the catechol moiety of the catechol estrogens as in 2-methoxyestradiol 3-methyl ether rendered the catechol estrogens inactive. The inhibitory potency of these compounds varied greatly depending on the structure associated with the catechol ring. Thus, compounds in which catechol is associated with an aliphatic side chain, such as dopamine, L-dopa, norepinephrine, and isoproterenol, were about 11- to 34-fold less potent than catechol. On the other hand, compounds in which catechol is associated either with a hydroaromatic ring system, as in apomorphine, or with an alicyclic ring system, as in catechol estrogens, were about 2- to 5-fold more potent than catechol. The inhibitory effect of dopamine, apomorphine, and catechol estrogens was not affected by specific D-1 or D-2 antagonist, indicating that they do not act via receptors for dopamine.

Adenylyl Cyclase Inhibitors↗
PubMed2004

Estrogen receptor-independent catechol estrogen binding activity: protein binding studies in wild-type, Estrogen receptor-alpha KO, and aromatase KO mice tissues.

Primary evidence for novel estrogen signaling pathways is based upon well-documented estrogenic responses not inhibited by estrogen receptor antagonists. In addition to 17beta-E2, the catechol estrogen 4-hydroxyestradiol (4OHE2) has been shown to elicit biological responses independent of classical estrogen receptors in estrogen receptor-alpha knockout (ERalphaKO) mice. Consequently, our research was designed to biochemically characterize the protein(s) that could be mediating the biological effects of catechol estrogens using enzymatically synthesized, radiolabeled 4-hydroxyestrone (4OHE1) and 4OHE2. Scatchard analyses identified a single class of high-affinity (K(d) approximately 1.6 nM), saturable cytosolic binding sites in several ERalphaKO estrogen-responsive tissues. Specific catechol estrogen binding was competitively inhibited by unlabeled catechol estrogens, but not by 17beta-E2 or the estrogen receptor antagonist ICI 182,780. Tissue distribution studies indicated significant binding differences both within and among various tissues in wild-type, ERalphaKO, and aromatase knockout female mice. Ligand metabolism experiments revealed extensive metabolism of labeled catechol estrogen, suggesting that catechol estrogen metabolites were responsible for the specific binding. Collectively, our data provide compelling evidence for the interaction of catechol estrogen metabolites with a novel binding protein that exhibits high affinity, specificity, and selective tissue distribution. The extensive biochemical characterization of this binding protein indicates that this protein may be a receptor, and thus may mediate ERalpha/beta-independent effects of catechol estrogens and their metabolites.

Animals↗
PubMed1994

Catechol estrogens are more potent antioxidants than estrogens for the Cu(2+)-catalyzed oxidation of low or high density lipoprotein: antioxidative effects of steroids on lipoproteins.

In order to clarify the mechanism of antiatherogenic action of several steroids such as estrogens, dehydroepiandrosterone (DHEA) and dexamethasone, we investigated the effects of various steroids on the copper (Cu2+)-catalyzed oxidation of low density lipoprotein (LDL) or high density lipoprotein (HDL) in 0.15 M NaCl by measuring thiobarbituric acid-reactive substances (TBARS). At a concentration of 10(-5) M, estrogens strongly protected against LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: estradiol (E2) (75%), estrone (E1) (35%) and estriol (E3) (30%). However, the corresponding metabolites of these estrogens, the catechol estrogens, had an even more protective effect on LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: 2-hydroxyestradiol (2-OHE2) (98%), 2-OHE1 (97%) and 2-OHE3 (96%). E2 and 2-OHE2 from 10(-7) M to 10(-5) M inhibited LDL oxidation in a dose-dependent manner, with a more marked effect for oxidation by 0.1 microM Cu2+ than by 0.5 microM Cu2+. 10(-5) M dexamethasone produced a slight (10%) but significant inhibition of LDL oxidation by 0.5 microM Cu2+. In addition, the estrogens and catechol estrogens were also effective in protecting against HDL oxidation by 0.5 microM Cu2+. Other steroids including DHEA and DHEA-sulfate had no antioxidative effects on either LDL or HDL in this system. These results indicate that estrogens and their metabolites, the catechol estrogens, exert antioxidative effects on both LDL and HDL. The catechol estrogens may be more important antioxidants than estrogens for both LDL and HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants↗
PubMed1986

Regioselective reaction of thiols with catechol estrogens and estrogen-O-quinones.

Incubations of [3H]estradiol and [3H]2-hydroxyestradiol (2-OHE2) with rat liver microsomes and mushroom tyrosinase were carried out in the presence of glutathione and 2-mercaptoethanol. A ratio of about 3.5:1 for the C-4 and C-1 thioether conjugates of 2-OHE2 was observed. Chemical reaction of estradiol-2, 3-O-quinone with various thiols showed that alkyl and phenyl thiols gave about a 1:1 ratio of C-4 to C-1 thioethers. However, reaction of the O-quinone with 4-nitrothiophenol gave a C-4/C-1 ratio of 0.25 while 4-bromothiophenol gave a C-4/C-1 ratio of 4.0. These studies suggest that the regioselectivity of the reaction of thiols with estrogen catechols and O-quinones may be dependent on the nature of the thiol compounds and less on steric hindrance.

Animals↗
PubMed2003

Aldehydic DNA lesions induced by catechol estrogens in calf thymus DNA.

The primary purpose of this research is to examine the hypothesis that reactive oxygen species generated by estrogen quinonoids are the main source for the formation of aldehydic DNA lesions (ADL) in genomic DNA. ADL induced by quinonoid metabolites of 17beta-estradiol (E2), e.g. 4-hydroxyestradiol (4-OH-E2), 2-hydroxyestradiol (2-OH-E2), estrogen-3,4-quinones (E2-3,4-Q) and estrogen- 2,3-quinone (E2-2,3-Q), were investigated in calf thymus DNA (CT-DNA) under physiological conditions. The abasic sites resulting from the spontaneous depurination-depyrimidination of the modified bases and the aldehydic base and sugar lesions resulting from the oxidative damage to deoxyribose moieties in the DNA molecules were measured by an aldehyde reactive probe and were estimated as the number of ADL per 106 nucleotides. With the addition of NADPH (100 micro M) and Cu(II) (20 micro M), nanomolar levels (100 nM) of 4-OH-E2 and 2-OH-E2 induced approximately 10-fold increases in the number of ADL over control (P<0.001). In parallel, increases in 8-oxoguanine were detected in DNA exposed to 4-OH-E2 and 2-OH-E2 (100 nM) plus Cu(II) and NADPH. Further investigation indicated that the ADL induced by estrogen catechols plus Cu(II) and NADPH were causally involved in the formation of hydrogen peroxide and Cu(I). Both E2-2,3-Q and E2-3,4-Q alone induced a 2-fold increase in the number of ADL over control (P<0.05) in CT-DNA at high concentrations (1 mM). Neither neutral thermal hydrolysis nor lower ionic strength of the reaction medium induced further increases in the number of ADL in E2-3,4-Q-modified CT-DNA. Conversely, with the inclusion of Cu(II) and NADPH, both E2-3,4-Q and E2-2,3-Q (1 micro M) induced parallel formation of DNA single strand breaks and approximately 20-fold increases in the number of ADL over control (P < 0.001). The data also demonstrated that the ADL induced by estrogen quinones with and without the presence of Cu(II) and NADPH contain 69 and 78% putrescine-excisable ADL in CT-DNA, respectively. Additionally, results of the ADL cleavage assay indicate that the ADL induced by estrogen quinones plus Cu(II) and NADPH in CT-DNA were predominantly T7 exonuclease-excisable (50%) and exonuclease III- excisable (20%) ADL, whereas the intact ADL, and other ADL accounted for 5 and 25%, respectively. These results suggest that the ADL induced by estrogen quinones in CT-DNA are derived from oxidative events rather than depurination/depyrimidination of labile estrogen quinone-DNA adducts. Overall, our results are at variance with the idea that depurination of estrogen quinone-DNA adducts is the major source for the formation of ADL in genomic DNA. We hypothesize that in addition to DNA adducts and oxidized bases, the ADL induced by estrogen quinonoid-mediated oxidative stress may play a role in estrogen-induced carcinogenicity.

Aldehydes↗
PubMed2000

Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O-methyltransferase-mediated metabolism of catechol estrogens.

The catechol metabolites of estradiol, 2- and 4-hydroxyestradiol (2-OHE(2) and 4-OHE(2), respectively) are potent signaling molecules and are hypothesized to be central to estrogen-linked carcinogenesis. Methylation by catechol-O-methyltransferase (COMT) is the principal means of catechol estrogen (CE) deactivation in the liver and other tissues. The present studies were conducted to determine the effects of PCBs and catechol metabolites of PCBs on the COMT-mediated catabolism of 4-OHE(2) and 2-OHE(2) in vitro and in vivo. Liver homogenates of female Sprague-Dawley rats treated with Aroclor 1254 for 21 days (5 mg/kg/day) showed a 30 and 40% reduction of COMT activity toward 2-OHE(2) and 4-OHE(2), respectively. Incubation of [(3)H]-beta-estradiol with these same liver homogenates, followed by HPLC analysis, demonstrated an elevation of CEs and a nearly complete reduction in levels of methylated catechol estrogens. In classical enzyme kinetics studies, COMT was demonstrated to have a high affinity for catechol PCBs, with K(m)'s approximately equivalent to those of CEs. Catechol PCBs were also potent inhibitors of CE O-methylation. These data suggest that PCBs may significantly alter the metabolism of catechol estrogens in vivo and that this effect may be mediated by catechol metabolites of PCBs. It is further speculated that methyltransferase inhibition by PCB catechols may contribute to PCB-mediated endocrine effects and liver carcinogenesis.

Animals↗
PubMed1988

Activation and irreversible binding of regiospecifically labeled catechol estrogen by rat liver microsomes: evidence for differential cytochrome P-450 catalyzed oxidations.

Estradiol and 2-hydroxyestradiol labeled with 3H at different positions in rings A or B were incubated with male rat liver microsomes, and their oxidative transformation was followed by the transfer of 3H into 3H2O. 14C-labeled estrogen or catechol estrogen was used to determine the fraction that becomes bound covalently to microsomal protein. The further metabolism of 2-hydroxyestradiol involves activation of the steroid at C-4 and, to a much lesser extent at C-1, by a cytochrome P-450 mediated reaction as indicated by the effects of NADPH, spermine, SKF-525A, and CO in the microsomal system. Glutathione promoted the loss of 3H from C-4 of either estradiol or 2-hydroxyestradiol but had less effect on this reaction at C-1 and inhibited it at C-6,7. It also abolished the irreversible binding of 14C-labeled estradiol and 2-hydroxyestradiol to microsomal protein. NADPH was needed specifically for glutathione to exert its effect both on the transfer of 3H into 3H2O and on the formation of water-soluble products from catechol estrogen by rat liver microsomes. It could not be replaced by NADP, NAD, or NADH. Ascorbic acid inhibited these enzymatic reactions but did not affect significantly the initial 2-hydroxylation of estradiol. Evidence is also provided for the further hydroxylation of 2-hydroxyestradiol at C-6 (or C-7). These results indicate that cytochrome P-450 activates catechol estrogens by an electron abstraction process.

Animals↗