4-Hydroxyestrone
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Names | |
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IUPAC name
3,4-Dihydroxyestra-1,3,5(10)-trien-17-one
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Systematic IUPAC name
(3aS,3bR,9bS,11aS)-6,7-Dihydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-1-one | |
Other names
4-OHE1; Estra-1,3,5(10)-triene-3,4-diol-17-one
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Identifiers | |
3D model (JSmol)
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ChEBI | |
ChEMBL | |
ChemSpider | |
PubChem CID
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UNII | |
CompTox Dashboard (EPA)
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Properties | |
C18H22O3 | |
Molar mass | 286.371 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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4-Hydroxyestrone (4-OHE1), also known as estra-1,3,5(10)-triene-3,4-diol-17-one, is an endogenous, naturally occurring catechol estrogen, neuroestrogen[1] and a minor metabolite of estrone and estradiol.[2][3][4] It is estrogenic, similarly to many other hydroxylated estrogen metabolites such as 2-hydroxyestradiol, 16α-hydroxyestrone, estriol (16α-hydroxyestradiol), and 4-hydroxyestradiol but unlike 2-hydroxyestrone.[2][5] 4-OHE1 is also categorized as a carcinogen.
Estrogen | ER RBA (%) | Uterine weight (%) | Uterotrophy | LH levels (%) | SHBG RBA (%) |
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Control | – | 100 | – | 100 | – |
Estradiol (E2) | 100 | 506 ± 20 | +++ | 12–19 | 100 |
Estrone (E1) | 11 ± 8 | 490 ± 22 | +++ | ? | 20 |
Estriol (E3) | 10 ± 4 | 468 ± 30 | +++ | 8–18 | 3 |
Estetrol (E4) | 0.5 ± 0.2 | ? | Inactive | ? | 1 |
17α-Estradiol | 4.2 ± 0.8 | ? | ? | ? | ? |
2-Hydroxyestradiol | 24 ± 7 | 285 ± 8 | +b | 31–61 | 28 |
2-Methoxyestradiol | 0.05 ± 0.04 | 101 | Inactive | ? | 130 |
4-Hydroxyestradiol | 45 ± 12 | ? | ? | ? | ? |
4-Methoxyestradiol | 1.3 ± 0.2 | 260 | ++ | ? | 9 |
4-Fluoroestradiola | 180 ± 43 | ? | +++ | ? | ? |
2-Hydroxyestrone | 1.9 ± 0.8 | 130 ± 9 | Inactive | 110–142 | 8 |
2-Methoxyestrone | 0.01 ± 0.00 | 103 ± 7 | Inactive | 95–100 | 120 |
4-Hydroxyestrone | 11 ± 4 | 351 | ++ | 21–50 | 35 |
4-Methoxyestrone | 0.13 ± 0.04 | 338 | ++ | 65–92 | 12 |
16α-Hydroxyestrone | 2.8 ± 1.0 | 552 ± 42 | +++ | 7–24 | <0.5 |
2-Hydroxyestriol | 0.9 ± 0.3 | 302 | +b | ? | ? |
2-Methoxyestriol | 0.01 ± 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. |
Chemical Structure Compared to Precursor
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/f/f4/Hydroxylation_of_17B-estradiol_into_4-hydroxyestrone_MugAl.jpg/220px-Hydroxylation_of_17B-estradiol_into_4-hydroxyestrone_MugAl.jpg)
The chemical structure of 4-OHE1 is a hydroxylated and oxidized form of 17β-estradiol (17β-E2). Specifically the 4th position of the estrogen ring in 17β-E2 is hydroxylated and the 17th position of the . Structural comparisons between 4-OHE1 and 17β-E2 show a congruent steroid backbone, but the additional hydroxyl group in 4-OHE1 changes its biochemical properties. 4-OHE1 exhibits enhanced carcinogenic activities within the human body as compared to 17β-E2.[6][7][8]
Biochemical Studies Related to 4-OHE1's Role as a Carcinogen and Neuroestrogen
[edit]4-OHE1 behaves similarly to 17β-E2 in electron emission processes. A study on electron emission of 17β-E2 demonstrated that 4-OHE1, as a secondary metabolite, can emit electrons in a similar mechanism post-UV excitation.[6] Additionally, studies related to the central nervous system (CNS) observed that the hydroxylation process in 17β-E2 also occurs in cerebral enzymes.[1]
In 2019, 4-OHE1 was detected within human urine from breast cancer patients, reinforcing its association with cancer. Moreover, 4-OHE1 has been found to confer chemotherepeutic resistance, against docetaxel.[7]
In 2020, studies comparing 17β-E2 and hydroxy esterone revealed that 4-OHE1 contributes to the cytoplasmic translocation of p53, a key tumor supressor protein, contributing to its role in cellular responses from stress and damage.[1]
In 2024, a study demonstrated 4-OHE1's role in cancer cell survival and its potential therapeutics for breast cancer treatment. 4-OHE1 acts as a ferroptosis inhibitor, a form of programmed cell death associated with cancer cell survival. Specifically, 4-OHE1 inhibits the protein disulfide isomerase (PDI), which is involved in the ferroptosis of specific breast cancer cells. By forming two hydrogen bonds with a crucial histidine residue in PDI, 4-OHE1 prevents cell death in these cells. Additionally, the 4-OHE1-PDI complex displays greater binding affinity but lower binding energy than a 17β-E2-PDI complex[8]
See also
[edit]- Estrogen conjugate
- Lipoidal estradiol
- 17β-estradiol (another name for Estradiol or E2)
References
[edit]- ^ a b c Choi, Hye Joung; Lee, Anthony J.; Kang, Ki Sung; Song, Ji Hoon; Zhu, Bao Ting (2020-04-29). "4-Hydroxyestrone, an Endogenous Estrogen Metabolite, Can Strongly Protect Neuronal Cells Against Oxidative Damage". Scientific Reports. 10 (1): 7283. Bibcode:2020NatSR..10.7283C. doi:10.1038/s41598-020-62984-y. ISSN 2045-2322. PMC 7190733. PMID 32350290.
- ^ a b Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. pp. 224, 232, 244–245, 249. ISBN 978-3-642-58616-3.
- ^ Rakel D (2012). Integrative Medicine. Elsevier Health Sciences. pp. 338–. ISBN 978-1-4377-1793-8.
- ^ Buchsbaum HJ (6 December 2012). The Menopause. Springer Science & Business Media. pp. 64–65. ISBN 978-1-4612-5525-3.
- ^ Bhavnani BR, Nisker JA, Martin J, Aletebi F, Watson L, Milne JK (2000). "Comparison of pharmacokinetics of a conjugated equine estrogen preparation (premarin) and a synthetic mixture of estrogens (C.E.S.) in postmenopausal women". Journal of the Society for Gynecologic Investigation. 7 (3): 175–83. doi:10.1016/s1071-5576(00)00049-6. PMID 10865186.
- ^ a b Getoff, Nikola; Gerschpacher, Marion; Hartmann, Johannes; Huber, Johannes C.; Schittl, Heike; Quint, Ruth Maria (2010-01-21). "The 4-hydroxyestrone: Electron emission, formation of secondary metabolites and mechanisms of carcinogenesis". Journal of Photochemistry and Photobiology B: Biology. 98 (1): 20–24. doi:10.1016/j.jphotobiol.2009.10.003. ISSN 1011-1344. PMC 2955241. PMID 19926488.
- ^ a b Miao, Suyu; Yang, Fengming; Wang, Ying; Shao, Chuchu; Zava, David T.; Ding, Qiang; Shi, Yuenian Eric (2019). "4-Hydroxy estrogen metabolite, causing genomic instability by attenuating the function of spindle-assembly checkpoint, can serve as a biomarker for breast cancer". American Journal of Translational Research. 11 (8): 4992–5007. ISSN 1943-8141. PMC 6731443. PMID 31497216.
- ^ a b Wang, Hongge; Hou, Ming-Jie; Liao, Lixi; Li, Peng; Chen, Tongxiang; Wang, Pan; Zhu, Bao Ting (2024-04-16). "Strong Protection by 4-Hydroxyestrone against Erastin-Induced Ferroptotic Cell Death in Estrogen Receptor-Negative Human Breast Cancer Cells: Evidence for Protein Disulfide Isomerase as a Mechanistic Target for Protection". Biochemistry. 63 (8): 984–999. doi:10.1021/acs.biochem.3c00261. ISSN 0006-2960. PMC 11025120. PMID 38569593.