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{{Chembox

| ImageFile = 2-Hydroxyestradiol.svg
| ImageSize = 200px
| ImageAlt =

| IUPACName = Estra-1,3,5(10)-triene-2,3,17β-triol
| SystematicName = (1''S'',3a''S'',3b''R'',9b''S'',11a''S'')-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1''H''-cyclopenta[''a'']phenanthrene-1,7,8-triol
| OtherNames = 2-OHE2

| Section1 = {{Chembox Identifiers
| CASNo = 362-05-0
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = AYU2L67YUU
| ChemSpiderID = 216475
| InChI = 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
| PubChem = 247304
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=CC(=C(C=C34)O)O
}}
| Section2 = {{Chembox Properties
| C=18|H=24|O=3
| Appearance =
| Density =
| MeltingPt =
| BoilingPt =
| Solubility =
}}
| Section3 = {{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
}}
}}
'''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]].<ref name="pmid9472688" />
{{TOC limit|2}}
==Biosynthesis==
Transformation of estradiol to 2-hydroxyestradiol is a major [[metabolism|metabolic]] pathway of estradiol in the [[liver]].<ref name="pmid9472688">{{cite journal | vauthors = Zhu BT, Conney AH | title = Functional role of estrogen metabolism in target cells: review and perspectives | journal = Carcinogenesis | volume = 19 | issue = 1 | pages = 1–27 | year = 1998 | pmid = 9472688 | doi = 10.1093/carcin/19.1.1| doi-access = free }}</ref> [[CYP1A2]] and [[CYP3A4]] are the major [[enzyme]]s catalyzing the 2-hydroxylation of estradiol.<ref name="pmid9472688" /> 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.<ref name="pmid9472688" /> Although estradiol is extensively converted into 2-hydroxyestradiol, circulating levels of 2-hydroxyestradiol and levels of 2-hydroxyestradiol in various tissues are very low.<ref name="pmid9472688" /> This may be due to rapid [[conjugation (biochemistry)|conjugation]] (O-[[methylation]], [[glucuronidation]], [[sulfonation]]) of 2-hydroxyestradiol followed by [[urine|urinary]] [[excretion]].<ref name="pmid9472688" />

==Biological activity==

===Estrogenic activity===
2-Hydroxyestradiol has approximately 7% and 11% of the [[affinity (pharmacology)|affinity]] of estradiol at the [[estrogen receptor]]s (ERs) [[ERα]] and [[ERβ]], respectively.<ref name="pmid9048584">{{cite journal | vauthors = Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA | title = Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta | journal = Endocrinology | volume = 138 | issue = 3 | pages = 863–70 | year = 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }}</ref> It dissociates from the estrogen receptors more rapidly than does estradiol.<ref name="pmid6658896">{{cite journal | vauthors = Barnea ER, MacLusky NJ, Naftolin F | title = Kinetics of catechol estrogen-estrogen receptor dissociation: a possible factor underlying differences in catechol estrogen biological activity | journal = Steroids | volume = 41 | issue = 5 | pages = 643–56 | date = May 1983 | pmid = 6658896 | doi = 10.1016/0039-128x(83)90030-2 | s2cid = 27048999 }}</ref> The steroid is only very weakly [[estrogen (medication)|estrogen]]ic, and is able to [[receptor antagonist|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]].<ref name="pmid9472688" /> It shows estrogenic activity in human [[breast cancer]] [[cell (biology)|cell]]s.<ref name="pmid8274412">{{cite journal | vauthors = Schütze N, Vollmer G, Tiemann I, Geiger M, Knuppen R | title = Catecholestrogens are MCF-7 cell estrogen receptor agonists | journal = J. Steroid Biochem. Mol. Biol. | volume = 46 | issue = 6 | pages = 781–9 | date = December 1993 | pmid = 8274412 | doi = 10.1016/0960-0760(93)90319-r | s2cid = 42692912 }}</ref> In addition to its activity at the nuclear ERs, 2-hydroxyestradiol is an [[receptor antagonist|antagonist]] of the [[G protein-coupled estrogen receptor]] (GPER) (100–1,000 μM).<ref name="pmid26023144">{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacol. Rev. | volume = 67 | issue = 3 | pages = 505–40 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}</ref>

{{Selected biological properties of endogenous estrogens in rats}}

===Catecholaminergic activity===
2-Hydroxyestradiol is a [[catechol]] estrogen and in this regard bears some structural resemblance to the [[catecholamine]]s [[dopamine]], [[norepinephrine]] (noradrenaline), and [[epinephrine]] (adrenaline).<ref name="pmid447670">{{cite journal | vauthors = Schaeffer JM, Hsueh AJ | title = 2-Hydroxyestradiol interaction with dopamine receptor binding in rat anterior pituitary | journal = J. Biol. Chem. | volume = 254 | issue = 13 | pages = 5606–8 | year = 1979 | doi = 10.1016/S0021-9258(18)50455-5 | pmid = 447670 | doi-access = free }}</ref> In accordance, 2-hydroxyestradiol has been found to interact with catecholamine systems.<ref name="pmid447670" /> The steroid is known to compete with catecholamines for binding to [[catechol O-methyltransferase]] and [[tyrosine hydroxylase]] and to directly and competitively [[enzyme inhibition|inhibit]] these [[enzyme]]s.<ref name="pmid447670" /><ref name="pmid2986765">{{cite journal | vauthors = Clopton JK, Gordon JH | title = The possible role of 2-hydroxyestradiol in the development of estrogen-induced striatal dopamine receptor hypersensitivity | journal = Brain Res. | volume = 333 | issue = 1 | pages = 1–10 | year = 1985 | pmid = 2986765 | doi = 10.1016/0006-8993(85)90117-9| s2cid = 25129158 }}</ref> In addition, 2-hydroxyestradiol has been found to displace [[spiperone]] from the [[D2 receptor|D2 receptor]] with approximately 50% of the affinity of dopamine, whereas estradiol, [[estrone]], and [[estriol]] and their other 2-[[hydroxylation|hydroxylated]] and 2-[[methoxy]]lated derivatives showed only weak or negligible inhibition.<ref name="pmid447670" /> Moreover, 2-hydroxyestradiol has been found to bind to the [[alpha-1 adrenergic receptor|α1-adrenergic receptor]] with slightly more than half the affinity of [[norepinephrine]].<ref name="pmid7086432">{{cite journal | vauthors = Paden CM, McEwen BS, Fishman J, Snyder L, DeGroff V | title = Competition by estrogens for catecholamine receptor binding in vitro | journal = J. Neurochem. | volume = 39 | issue = 2 | pages = 512–20 | year = 1982 | pmid = 7086432 | doi = 10.1111/j.1471-4159.1982.tb03974.x| s2cid = 20391880 }}</ref> However, although these affinities are comparable to those of dopamine and norepinephrine, they are nonetheless in the double-digit [[micromolar]] range.<ref name="pmid447670" /><ref name="pmid7086432" />

2-Hydroxyestradiol has been found to increase prolactin secretion when administered [[intravenous administration|intravenously]] to women.<ref name="pmid6772666">{{cite journal | vauthors = Adashi EY, Casper RF, Fishman J, Yen SS | title = Stimulatory effect of 2-hydroxyestradiol on prolactin release in hypogonadal women | journal = J. Clin. Endocrinol. Metab. | volume = 51 | issue = 2 | pages = 413–5 | year = 1980 | pmid = 6772666 | doi = 10.1210/jcem-51-2-413 }}</ref> It was noted that this could be due to 2-hydroxyestradiol binding to and antagonizing the D2 receptor.<ref name="pmid6772666" /> 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.<ref name="pmid6772666" /> 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.<ref name="pmid6772666" /> 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.<ref name="pmid6772666" /> In any case, these findings argue against the notion of major interactions of 2-hydroxyestradiol with the dopamine system.<ref name="pmid6772666" />

===Genotoxicity===
2-Hydroxyestradiol, as well as 2-hydroxyestrone and [[4-hydroxyestradiol]], can undergo metabolic [[redox cycling]] to generate [[free radical]]s like [[superoxide]] and reactive estrogen [[semiquinone]]/[[quinone]] [[metabolic intermediate|intermediate]]s.<ref name="pmid9472688" /> These metabolites may damage [[DNA]] and other [[cell (biology)|cell]]ular components.<ref name="pmid9472688" /> 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.<ref name="pmid9472688" /> It has been suggested that the lack of tumorigenesis of 2-hydroxyestrone is due to its rapid clearance.<ref name="pmid9472688" /> In addition, its metabolite [[2-methoxyestradiol]] is a very potent inhibitor of [[tumor]] growth and [[angiogenesis]], and this may contribute as well.<ref name="pmid9472688" />

===Production of 2-methoxyestradiol===
2-Hydroxyestradiol has been identified as a [[prodrug]] of [[2-methoxyestradiol]], a [[biotransformation|transformation]] which is very efficiently catalyzed by [[catechol O-methyltransferase]] in the [[liver]].<ref name="pmid15777138">{{cite journal | vauthors = Bastian I | title = The tsunami of tuberculosis | journal = Med. J. Aust. | volume = 182 | issue = 6 | pages = 263–4 | year = 2005 | pmid = 15777138 | doi = 10.5694/j.1326-5377.2005.tb06696.x| s2cid = 38176855 }}</ref> 2-Methoxyestradiol is not estrogenic but is a potent [[angiogenesis inhibitor]] and [[agonist]] of the [[GPER]] with potential therapeutic implications in [[cancer]].<ref name="ThekkumkaraSnyder2016">{{cite book|last1=Thekkumkara|first1=Thomas|title=Estrogen Receptors|last2=Snyder|first2=Russell|last3=Karamyan|first3=Vardan T.|chapter=Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER)|volume=1366|year=2016|pages=11–17|issn=1064-3745|doi=10.1007/978-1-4939-3127-9_2|pmid=26585123|series=Methods in Molecular Biology|isbn=978-1-4939-3126-2}}</ref>

===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.<ref name="RubanyiKauffman2003">{{cite book|author1=Gabor M. Rubanyi|author2=R Kauffman|title=Estrogen and the Vessel Wall|url=https://books.google.com/books?id=U6WU25VeOBsC&pg=PA88|date=2 September 2003|publisher=CRC Press|isbn=978-0-203-30393-1|pages=88–}}</ref>{{dubious|reason=Seems to contradict redox cycling issue (especially for the 4-OH mention)!|date=December 2022}}

==History==
2-Hydroxyestradiol was identified as a metabolite of estradiol in 1960.<ref name="pmid379882">{{cite journal | vauthors = Bolt HM | title = Metabolism of estrogens--natural and synthetic | journal = Pharmacol. Ther. | volume = 4 | issue = 1 | pages = 155–81 | year = 1979 | pmid = 379882 | doi = 10.1016/0163-7258(79)90018-4}}</ref>

==References==
{{Reflist}}

{{Endogenous steroids}}
{{Estrogen receptor modulators}}
{{Monoamine metabolism modulators}}

{{DEFAULTSORT:Hydroxyestradiol, 2-}}

[[Category:Catechol-O-methyltransferase inhibitors]]
[[Category:Estranes]]
[[Category:Estrogens]]
[[Category:Human metabolites]]
[[Category:Selective estrogen receptor modulators]]
[[Category:Steroid hormones]]
[[Category:Tyrosine hydroxylase inhibitors]]

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