Disease relevance of 5976-61-4

• An elevated ratio of 4-/2-hydroxyestradiol formation in neoplastic mammary tissue may therefore provide a useful marker of benign or malignant breast tumors and may indicate a mechanistic role of 4-hydroxyestradiol in tumor development [1].
• 2-Hydroxyestradiol induced tumors in 12% of the mice, but 4-hydroxyestradiol was the most carcinogenic estrogen, with a 66% incidence of uterine adenocarcinoma [2].
• The Val432 allele has a higher efficiency of conversion of estradiol to 4-hydroxyestradiol and has been reported to increase the risk of ovarian cancer [3].
• We investigated the reactivity of LPO towards five molecules: 17-beta-estradiol (a natural hormone), diethylstilbestrol (a synthetic drug, supplied to pregnant women for preventing spontaneous abortion), exestrol (a synthetic antigonadotropic estrogen), 2-OH- and 4-OH-estradiol (catabolic products of estradiol) [4].
• This paper describes the induction of uterine eosinophilia as well as of deep endometrial edema and increase of uterine wet weight in the immature rat by the catecholestrogens 2-OH-estradiol and 4-OH-estradiol [5].

High impact information on 5976-61-4

• Several types of direct and indirect free radical-mediated DNA damage are induced by E2, 4-hydroxyestradiol, or its corresponding quinone in cell-free systems, in cells in culture, and/or in vivo [6].
• Catechol estrogens (2- or 4-hydroxyestradiol and 2- or 4-hydroxyestrone) are chemically reactive estrogen metabolites that are O-methylated to less polar monomethyl ethers by catechol-O-methyltransferase, an enzyme present in many tissues such as the liver, kidney, brain, placenta, uterus, and mammary gland [7].
• Electron spin resonance spectroscopy has been used to demonstrate production of semiquinone-free radicals from the oxidation of the catechol estrogens 2- and 4-hydroxyestradiol and 2,6- and 4,6-dihydroxyestradiol [8].
• Results and Conclusions: PKR was increased in 2-ME-treated MG63 cells, whereas 17beta-estradiol, 4-hydroxyestradiol, and 16alpha-hydroxyestradiol, which do not induce cell death, had no effect on PKR protein levels [9].
• Our results show that GSH, DTT, and DHLA inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH showing the best potential [10].

Chemical compound and disease context of 5976-61-4

• The effect of airborne frying-meat emission particulate (FMEP) on metabolism of 17beta-estradiol (E(2)) to potentially toxic catechol estrogens 2- and 4-hydroxyestradiol (2- and 4-OH-E(2)) was determined using human lung adenocarcinoma CL5 cells treated with organic extracts of beef FMEP [11].

Biological context of 5976-61-4

• S-Adenosyl-L-homocysteine, produced by the methylation of catecholestrogens, noncompetitively inhibited the O-methylation of 2- and 4-hydroxyestradiol by hamster kidney cytosolic catechol O-methyltransferase (IC50 approximately 10-14 microM) [12].
• We have demonstrated that DNA strand breakage is induced synergistically when pBR322 plasmid DNA is incubated in the presence of both a nitric oxide (NO)-releasing compound (diethylamine NONOate, etc.) and a catechol-estrogen (2- or 4-hydroxyestradiol or -hydroxyestrone) [13].
• Widely differing efficacies in the induction of progestin binding sites were observed between the dibenzoate esters of 2- and 4-hydroxyestradiol [14].
• Since 4-hydroxyestradiol has been implicated in hormonal carcinogenesis and CYP1B1 is expressed in target tissues, the data presented demonstrate that polymorphisms in CYP1B1 have the potential to affect disease susceptibility [15].
• Furthermore, the mutational spectrum of 4-hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E(2)-3,4-quinone to form a significant fraction of DNA adducts at adenines [16].

Anatomical context of 5976-61-4

• 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 [17].
• The percentages of incubated estradiol hydroxylated at C-atom 4 (4-hydroxyestradiol and 4-hydroxyestrone) were 0.5 in the cortex, 0.4% in the hypothalamus, .1% in the pituitary, and 0.5% in the liver [18].
• Rates of O-methylation of 2- and 4-hydroxyestrone by hamster kidney cytosol were comparable to those of 2- and 4-hydroxyestradiol [19].
• Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells [20].
• Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo [21].

Associations of 5976-61-4 with other chemical compounds

• Therefore, this study was undertaken to determine the ability of different thiol agents (GSH, NAC, DTT, DHLA) to either inhibit or enhance the level of DNA damage induced by the H(2)O(2) generating system 4-hydroxyestradiol/Cu(II) [10].
• Tritium-labelled receptor complexes were demonstrated in KCl extracts of purified nuclei from pituitary and hypothalamic tissue 1 h after intravenous injection of 0.1 mCi tritiated 2- or 4-hydroxyestradiol [22].
• At a 15 microM 4-hydroxyestradiol concentration, the IC50 values for epinephrine and for dopamine were approximately 1200 and 3000 microM, respectively [23].
• In the presence of S-adenosylmethionine, 2- or 4-hydroxyestradiol (2-OHE2 or 4-OHE2) was incubated with blood lysate obtained from rats (five strains), guinea pigs, mice, rabbits, dogs, monkeys, and humans, respectively [24].
• In contrast, prooxidant effects such as 8-hydroxylation of guanine bases of DNA have been induced by various estrogens in hamsters and by 4-hydroxyestradiol or -estrone and a microsomal activating system in vitro [25].

Gene context of 5976-61-4

• Taken together, these observations suggest that 4-hydroxyestradiol activates the ARE by a PI3-kinase-Nrf2 dependent mechanism, not involving ER [26].
• A selective phosphatidylinositol 3-kinase (PI3-kinase) inhibitor (LY294002) blocked 4-hydroxyestradiol-induced Nrf2 nuclear translocation and NQO1 activity induction in IMR-32 cells [26].
• Nrf2, however, was very important in the 4-hydroxyestradiol-induced ARE activation [26].
• Polymorphisms in P450 CYP1B1 affect the conversion of estradiol to the potentially carcinogenic metabolite 4-hydroxyestradiol [15].
• 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) [27].

Analytical, diagnostic and therapeutic context of 5976-61-4

• The metabolism of estradiol 17-sulfate (ES) by hepatic microsomes of female rats produced four new metabolites in addition to 2- and 4-hydroxyestradiol 17-sulfates (2- and 4-OH-ES), which were detected on an HPLC chromatogram [28].
• After 14 days of treatment, groups which were treated with estradiol, 2-hydroxyestradiol or 4-hydroxyestradiol had significantly higher striatal dopamine levels and had gained significantly less weight when compared to the control group [29].
• We have developed a gas chromatography/mass spectrometry (GC/MS) assay to measure 17beta-estradiol (E) and its biologically active metabolites 2-hydroxyestradiol (2OHE) and 4-hydroxyestradiol (4OHE), and 2-methoxyestradiol (2MEOE) and 4-methoxyestradiol (4MEOE) in rat plasma [30].
• High performance liquid chromatography was coupled to detection of radioactive products in a flowing system to separate the 2- and 4-hydroxyestradiol (2- and 4-OH-E2) formed from estradiol [31].
• Sucrose density gradient centrifugation revealed that both 2- and 4-hydroxyestradiol inhibited the binding of estradiol-17 beta to both the 4S and 8S isoforms of the estrogen receptor in a competitive manner, with a Ki = 0.94 nM for 2-hydroxyestradiol and a Ki = 0.48 nM for 4-hydroxyestradiol [32].

References