2-Hydroxyestradiol

2-Hydroxyestradiol
Names
Preferred IUPAC name
(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
Other names
2-OHE2; Estra-1,3,5(10)-triene-2,3,17β-triol
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.160.393
Edit this at Wikidata
PubChem CID
UNII
InChI
  • 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
SMILES
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=CC(=C(C=C34)O)O
Properties
Chemical formula
 C18H24O3
Molar mass 288.387 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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.[1]

Biosynthesis

Transformation of estradiol to 2-hydroxyestradiol is a major metabolic pathway of estradiol in the liver.[1] CYP1A2 and CYP3A4 are the major enzymes catalyzing the 2-hydroxylation of estradiol.[1] 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.[1] Although estradiol is extensively converted into 2-hydroxyestradiol, circulating levels of 2-hydroxyestradiol and levels of 2-hydroxyestradiol in various tissues are very low.[1] This may be due to rapid conjugation (O-methylation, glucuronidation, sulfonation) of 2-hydroxyestradiol followed by urinary excretion.[1]

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.[2] It dissociates from the estrogen receptors more rapidly than does estradiol.[3] 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.[1] It shows estrogenic activity in human breast cancer cells.[4] 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).[5]

Selected biological properties of endogenous estrogens in rats
EstrogenER RBA (%)Uterine weight (%)UterotrophyLH levels (%)SHBG RBA (%)
Control–100–100–
Estradiol100506 ± 20+++12–19100
Estrone11 ± 8490 ± 22+++ ?20
Estriol10 ± 4468 ± 30+++8–183
Estetrol0.5 ± 0.2 ?Inactive ?1
17α-Estradiol4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol0.05 ± 0.04101Inactive ?130
4-Hydroxyestradiol45 ± 12 ? ? ? ?
4-Methoxyestradiol1.3 ± 0.2260++ ?9
4-Fluoroestradiola180 ± 43 ?+++ ? ?
2-Hydroxyestrone1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone11 ± 4351++21–5035
4-Methoxyestrone0.13 ± 0.04338++65–9212
16α-Hydroxyestrone2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol0.9 ± 0.3302+b ? ?
2-Methoxyestriol0.01 ± 0.00 ?Inactive ?4
Notes: Values are mean ± SD or range. ER RBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes: a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

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).[6] In accordance, 2-hydroxyestradiol has been found to interact with catecholamine systems.[6] 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.[6][7] 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.[6] Moreover, 2-hydroxyestradiol has been found to bind to the α1-adrenergic receptor with slightly more than half the affinity of norepinephrine.[8] However, although these affinities are comparable to those of dopamine and norepinephrine, they are nonetheless in the double-digit micromolar range.[6][8]

2-Hydroxyestradiol has been found to increase prolactin secretion when administered intravenously to women.[9] It was noted that this could be due to 2-hydroxyestradiol binding to and antagonizing the D2 receptor.[9] 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.[9] 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.[9] 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.[9] In any case, these findings argue against the notion of major interactions of 2-hydroxyestradiol with the dopamine system.[9]

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.[1] These metabolites may damage DNA and other cellular components.[1] 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.[1] It has been suggested that the lack of tumorigenesis of 2-hydroxyestrone is due to its rapid clearance.[1] In addition, its metabolite 2-methoxyestradiol is a very potent inhibitor of tumor growth and angiogenesis, and this may contribute as well.[1]

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.[10] 2-Methoxyestradiol is not estrogenic but is a potent angiogenesis inhibitor and agonist of the GPER with potential therapeutic implications in cancer.[11]

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.[12]

History

2-Hydroxyestradiol was identified as a metabolite of estradiol in 1960.[13]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Zhu BT, Conney AH (1998). "Functional role of estrogen metabolism in target cells: review and perspectives". Carcinogenesis. 19 (1): 1–27. doi:10.1093/carcin/19.1.1. PMID 9472688.
  2. ↑ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584.
  3. ↑ Barnea ER, MacLusky NJ, Naftolin F (May 1983). "Kinetics of catechol estrogen-estrogen receptor dissociation: a possible factor underlying differences in catechol estrogen biological activity". Steroids. 41 (5): 643–56. doi:10.1016/0039-128x(83)90030-2. PMID 6658896. S2CID 27048999.
  4. ↑ Schütze N, Vollmer G, Tiemann I, Geiger M, Knuppen R (December 1993). "Catecholestrogens are MCF-7 cell estrogen receptor agonists". J. Steroid Biochem. Mol. Biol. 46 (6): 781–9. doi:10.1016/0960-0760(93)90319-r. PMID 8274412. S2CID 42692912.
  5. ↑ Prossnitz ER, Arterburn JB (July 2015). "International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators". Pharmacol. Rev. 67 (3): 505–40. doi:10.1124/pr.114.009712. PMC 4485017. PMID 26023144.
  6. 1 2 3 4 5 Schaeffer JM, Hsueh AJ (1979). "2-Hydroxyestradiol interaction with dopamine receptor binding in rat anterior pituitary". J. Biol. Chem. 254 (13): 5606–8. doi:10.1016/S0021-9258(18)50455-5. PMID 447670.
  7. ↑ Clopton JK, Gordon JH (1985). "The possible role of 2-hydroxyestradiol in the development of estrogen-induced striatal dopamine receptor hypersensitivity". Brain Res. 333 (1): 1–10. doi:10.1016/0006-8993(85)90117-9. PMID 2986765. S2CID 25129158.
  8. 1 2 Paden CM, McEwen BS, Fishman J, Snyder L, DeGroff V (1982). "Competition by estrogens for catecholamine receptor binding in vitro". J. Neurochem. 39 (2): 512–20. doi:10.1111/j.1471-4159.1982.tb03974.x. PMID 7086432. S2CID 20391880.
  9. 1 2 3 4 5 6 Adashi EY, Casper RF, Fishman J, Yen SS (1980). "Stimulatory effect of 2-hydroxyestradiol on prolactin release in hypogonadal women". J. Clin. Endocrinol. Metab. 51 (2): 413–5. doi:10.1210/jcem-51-2-413. PMID 6772666.
  10. ↑ Bastian I (2005). "The tsunami of tuberculosis". Med. J. Aust. 182 (6): 263–4. doi:10.5694/j.1326-5377.2005.tb06696.x. PMID 15777138. S2CID 38176855.
  11. ↑ Thekkumkara, Thomas; Snyder, Russell; Karamyan, Vardan T. (2016). "Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER)". Estrogen Receptors. Methods in Molecular Biology. Vol. 1366. pp. 11–17. doi:10.1007/978-1-4939-3127-9_2. ISBN 978-1-4939-3126-2. ISSN 1064-3745. PMID 26585123.
  12. ↑ Gabor M. Rubanyi; R Kauffman (2 September 2003). Estrogen and the Vessel Wall. CRC Press. pp. 88–. ISBN 978-0-203-30393-1.
  13. ↑ Bolt HM (1979). "Metabolism of estrogens--natural and synthetic". Pharmacol. Ther. 4 (1): 155–81. doi:10.1016/0163-7258(79)90018-4. PMID 379882.
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.