2-Hydroxyestradiol

2-Hydroxyestradiol.svg skin-invert-image 200px Estra-1,3,5(10)-triene-2,3,17β-triol (1S,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,7,8-triol 2-OHE2 362-05-0 correct CAS correct FDA AYU2L67YUU 216475 1S/C18H24O3/c1-18-7-6-11-12(14(18)4-5-17(18)21)3-2-10-8-15(19)16(20)9-13(10)11/h8-9,11-12,14,17,19-21H,2-7H2,1H3/t11-,12+,14-,17-,18-/m0/s1 247304 Oc1c(O)cc2[C@H]3CC[C@]4(C)[C@]5(CC[C@H]4[C@@H]3CCc2c1).O5 18 24 3 2-Hydroxyestradiol (2-OHE2), also known as estra-1,3,5(10)-triene-2,3,17β-triol, is an endogenous steroid, catechol estrogen, and metabolite of estradiol, as well as a positional isomer of estriol. 2 Biosynthesis Transformation of estradiol to 2-hydroxyestradiol is a major metabolic pathway of estradiol in the liver. Zhu BT, Conney AH Functional role of estrogen metabolism in target cells: review and perspectives Carcinogenesis 19 1 1–27 1998 9472688 10.1093/carcin/19.1.1 free CYP1A2 and CYP3A4 are the major enzymes catalyzing the 2-hydroxylation of estradiol. Conversion of estradiol into 2-hydroxyestradiol has also been detected in the uterus, breast, kidney, brain, and pituitary gland, as well as the placenta, and may similarly be mediated by cytochrome P450 enzymes. Although estradiol is extensively converted into 2-hydroxyestradiol, circulating levels of 2-hydroxyestradiol and levels of 2-hydroxyestradiol in various tissues are very low. This may be due to rapid conjugation (O-methylation, glucuronidation, sulfonation) of 2-hydroxyestradiol followed by urinary excretion. Biological activity Estrogenic activity 2-Hydroxyestradiol has approximately 7% and 11% of the affinity of estradiol at the estrogen receptors (ERs) ERα and ERβ, respectively. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta Endocrinology 138 3 863–70 1997 9048584 10.1210/endo.138.3.4979 free It dissociates from the estrogen receptors more rapidly than does estradiol. Barnea ER, MacLusky NJ, Naftolin F Kinetics of catechol estrogen-estrogen receptor dissociation: a possible factor underlying differences in catechol estrogen biological activity Steroids 41 5 643–56 May 1983 6658896 10.1016/0039-128x(83)90030-2 27048999 The steroid is only very weakly estrogenic, and is able to antagonize the estrogenic effects of estradiol, indicating that its intrinsic activity at the estrogen receptor is less than that of estradiol and hence that it possesses the profile of a selective estrogen receptor modulator. It shows estrogenic activity in human breast cancer cells. Schütze N, Vollmer G, Tiemann I, Geiger M, Knuppen R Catecholestrogens are MCF-7 cell estrogen receptor agonists J. Steroid Biochem. Mol. Biol. 46 6 781–9 December 1993 8274412 10.1016/0960-0760(93)90319-r 42692912 In addition to its activity at the nuclear ERs, 2-hydroxyestradiol is an antagonist of the G protein-coupled estrogen receptor (GPER) (100–1,000 μM). Prossnitz ER, Arterburn JB International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators Pharmacol. Rev. 67 3 505–40 July 2015 26023144 4485017 10.1124/pr.114.009712 Catecholaminergic activity 2-Hydroxyestradiol is a catechol estrogen and in this regard bears some structural resemblance to the catecholamines dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Schaeffer JM, Hsueh AJ 2-Hydroxyestradiol interaction with dopamine receptor binding in rat anterior pituitary J. Biol. Chem. 254 13 5606–8 1979 10.1016/S0021-9258(18)50455-5 447670 free In accordance, 2-hydroxyestradiol has been found to interact with catecholamine systems. The steroid is known to compete with catecholamines for binding to catechol O-methyltransferase and tyrosine hydroxylase and to directly and competitively inhibit these enzymes. Clopton JK, Gordon JH The possible role of 2-hydroxyestradiol in the development of estrogen-induced striatal dopamine receptor hypersensitivity Brain Res. 333 1 1–10 1985 2986765 10.1016/0006-8993(85)90117-9 25129158 In addition, 2-hydroxyestradiol has been found to displace spiperone from the D2 receptor with approximately 50% of the affinity of dopamine, whereas estradiol, estrone, and estriol and their other 2-hydroxylated and 2-methoxylated derivatives showed only weak or negligible inhibition. Moreover, 2-hydroxyestradiol has been found to bind to the α1-adrenergic receptor with slightly more than half the affinity of norepinephrine. Paden CM, McEwen BS, Fishman J, Snyder L, DeGroff V Competition by estrogens for catecholamine receptor binding in vitro J. Neurochem. 39 2 512–20 1982 7086432 10.1111/j.1471-4159.1982.tb03974.x 20391880 However, although these affinities are comparable to those of dopamine and norepinephrine, they are nonetheless in the double-digit micromolar range. 2-Hydroxyestradiol has been found to increase prolactin secretion when administered intravenously to women. Adashi EY, Casper RF, Fishman J, Yen SS Stimulatory effect of 2-hydroxyestradiol on prolactin release in hypogonadal women J. Clin. Endocrinol. Metab. 51 2 413–5 1980 6772666 10.1210/jcem-51-2-413 It was noted that this could be due to 2-hydroxyestradiol binding to and antagonizing the D2 receptor. However, the researchers argued against this possibility because it was delayed (by several hours) and of relatively small magnitude, whereas established D2 receptor antagonists promptly induce marked increases in prolactin levels. The researchers also argued against the possibility that it was due to inhibition of dopamine biosynthesis by 2-hydroxyestradiol because 2-hydroxyestrone, which inhibits tyrosine hydroxylase similarly to 2-hydroxyestradiol, showed no such increase in prolactin secretion. The researchers concluded that the most likely explanation was that the increase was mediated by the estrogenic activity of 2-hydroxyestradiol, as similar increments in prolactin levels had been observed with estradiol. In any case, these findings argue against the notion of major interactions of 2-hydroxyestradiol with the dopamine system. Genotoxicity 2-Hydroxyestradiol, as well as 2-hydroxyestrone and 4-hydroxyestradiol, can undergo metabolic redox cycling to generate free radicals like superoxide and reactive estrogen semiquinone/quinone intermediates. These metabolites may damage DNA and other cellular components. However, 2-hydroxyestradiol shows little or no tumorigenic activity in the male Syrian hamster kidney and there is evidence that 2-hydroxyestradiol may actually decrease tumorigenesis in estrogen-sensitive tissues. It has been suggested that the lack of tumorigenesis of 2-hydroxyestrone is due to its rapid clearance. In addition, its metabolite 2-methoxyestradiol is a very potent inhibitor of tumor growth and angiogenesis, and this may contribute as well. Production of 2-methoxyestradiol 2-Hydroxyestradiol has been identified as a prodrug of 2-methoxyestradiol, a transformation which is very efficiently catalyzed by catechol O-methyltransferase in the liver. Bastian I The tsunami of tuberculosis Med. J. Aust. 182 6 263–4 2005 15777138 10.5694/j.1326-5377.2005.tb06696.x 38176855 2-Methoxyestradiol is not estrogenic but is a potent angiogenesis inhibitor and agonist of the GPER with potential therapeutic implications in cancer.Thekkumkara Thomas Estrogen Receptors Snyder Russell Karamyan Vardan T. Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER) 1366 2016 11–17 1064-3745 10.1007/978-1-4939-3127-9_2 26585123 Methods in Molecular Biology 978-1-4939-3126-2 Antioxidant activity Similarly to other steroidal estrogens, 2-hydroxyestradiol is an antioxidant, but the catechol estrogens (2- and 4-hydroxylated estrogens) like 2-hydroxyestradiol are considered to be the most potent in terms of antioxidant activity.Gabor M. Rubanyi R Kauffman Estrogen and the Vessel Wall https://books.google.com/books?id=U6WU25VeOBsC&pg=PA88 2 September 2003 CRC Press 978-0-203-30393-1 88–Seems to contradict redox cycling issue (especially for the 4-OH mention)! December 2022 In FENIX (fluorescence-enabled inhibited autoxidation) assays, a potent radical trapping antioxidant (RTA) activity of 2-hydroxyestradiol and 4-hydroxyestradiol was confirmed. Via this potent RTA activity, these molecules can exert a direct inhibition of ferroptosis, an iron-dependent cell death.Tonnus Wulf Maremonti Francesca Gavali Shubhangi Schlecht Marlena Nastassja Gembardt Florian Belavgeni Alexia Leinung Nadja Flade Karolin Bethe Natalie Traikov Sofia Haag Anne Schilling Danny Penkov Sider Mallais Melodie Gaillet Christine 2025-08-13 Multiple oestradiol functions inhibit ferroptosis and acute kidney injury https://www.nature.com/articles/s41586-025-09389-x Nature en 1–9 10.1038/s41586-025-09389-x 1476-4687 subscription 12460175 History 2-Hydroxyestradiol was identified as a metabolite of estradiol in 1960. Bolt HM Metabolism of estrogens--natural and synthetic Pharmacol. Ther. 4 1 155–81 1979 379882 10.1016/0163-7258(79)90018-4 References Category:Catechol-O-methyltransferase inhibitors Category:Estranes Category:Estrogens Category:Human metabolites Category:Selective estrogen receptor modulators Category:Steroid hormones Category:Tyrosine hydroxylase inhibitors