4-Hydroxyestroneのソースを表示

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| ImageFile = 4-Hydroxyestrone.svg
| ImageSize = 200px
| ImageAlt =
<!-- Names -->
| IUPACName = 3,4-Dihydroxyestra-1,3,5(10)-trien-17-one
| SystematicName = (3a''S'',3b''R'',9b''S'',11a''S'')-6,7-Dihydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1''H''-cyclopenta[''a'']phenanthren-1-one
| OtherNames = 4-OHE1; Estra-1,3,5(10)-triene-3,4-diol-17-one
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| Section1 = {{Chembox Identifiers
| CASNo = 3131-23-5
| ChEBI = 87602
| ChEMBL = 1743300
| ChemSpiderID = 8146843
| PubChem = 9971251
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CCC4=C3C=CC(=C4O)O
| StdInChI = 1S/C18H22O3/c1-18-9-8-11-10-4-6-15(19)17(21)13(10)3-2-12(11)14(18)5-7-16(18)20/h4,6,11-12,14,19,21H,2-3,5,7-9H2,1H3/t11-,12-,14+,18+/m1/s1
| StdInChIKey = XQZVQQZZOVBNLU-QDTBLXIISA-N
| UNII = 3MN57C55S2
  }}
| Section2 = {{Chembox Properties
| C=18 | H=22 | O=3
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| Section3 = {{Chembox Hazards
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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]], [[natural product|naturally occurring]] [[catechol estrogen]], [[doi:10.1038/s41598-020-62984-y|neuroestrogen]]<ref name=":3">{{Cite journal |last1=Choi |first1=Hye Joung |last2=Lee |first2=Anthony J. |last3=Kang |first3=Ki Sung |last4=Song |first4=Ji Hoon |last5=Zhu |first5=Bao Ting |date=2020-04-29 |title=4-Hydroxyestrone, an Endogenous Estrogen Metabolite, Can Strongly Protect Neuronal Cells Against Oxidative Damage |journal=Scientific Reports |language=en |volume=10 |issue=1 |pages=7283 |doi=10.1038/s41598-020-62984-y |issn=2045-2322 |pmc=7190733 |pmid=32350290|bibcode=2020NatSR..10.7283C }}</ref> and a minor [[metabolite]] of [[estrone]] and [[estradiol]].<ref name="OettelSchillinger2012">{{cite book | first1 = Michael | last1 = Oettel | first2 = Ekkehard | last2 = Schillinger | name-list-style = vanc |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA232|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3|pages=224, 232, 244–245, 249}}</ref><ref name="Rakel2012">{{cite book | first = David | last = Rakel | name-list-style = vanc |title=Integrative Medicine|url=https://books.google.com/books?id=jlVtJzBwAcEC&pg=PA338|year=2012|publisher=Elsevier Health Sciences|isbn=978-1-4377-1793-8|pages=338–}}</ref><ref name="Buchsbaum2012">{{cite book| vauthors = Buchsbaum HJ |title=The Menopause|url=https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA65|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5525-3|pages=64–65}}</ref> It is [[estrogen]]ic, similarly to many other hydroxylated estrogen metabolites such as [[2-hydroxyestradiol]], [[16α-hydroxyestrone]], [[estriol]] (16α-hydroxyestradiol), and [[4-hydroxyestradiol]] but unlike [[2-hydroxyestrone]].<ref name="OettelSchillinger2012" /><ref name="pmid10865186">{{cite journal | vauthors = Bhavnani BR, Nisker JA, Martin J, Aletebi F, Watson L, Milne JK | title = Comparison of pharmacokinetics of a conjugated equine estrogen preparation (premarin) and a synthetic mixture of estrogens (C.E.S.) in postmenopausal women | journal = Journal of the Society for Gynecologic Investigation | volume = 7 | issue = 3 | pages = 175–83 | year = 2000 | pmid = 10865186 | doi =  10.1016/s1071-5576(00)00049-6}}</ref> 4-OHE1 is also categorized as a [[carcinogen]].{{Selected biological properties of endogenous estrogens in rats}}

== Chemical Structure Compared to Precursor ==
[[File:Hydroxylation of 17B-estradiol into 4-hydroxyestrone MugAl.jpg|thumb|The hydroxylation (and indirect oxidation) of 17B-estradiol into 4-hydroxyestrone.]]
The chemical structure of 4-OHE1 is a [[Hydroxylation|hydroxylated]] and oxidized form of [https://pubchem.ncbi.nlm.nih.gov/compound/Estradiol 17β-estradiol] ([[Estradiol|17β-E2]]). Specifically the 4th position of the [[estrogen]] ring in [[Estradiol|17β-E2]] is hydroxylated and the 17th position of the . Structural comparisons between 4-OHE1 and [[Estradiol|17β-E2]] show a congruent [[steroid]] backbone, but the additional [[Hydroxy group|hydroxyl]] group in 4-OHE1 changes its biochemical properties. 4-OHE1 exhibits enhanced [[carcinogen]]<nowiki/>ic activities within the human body as compared to [[Estradiol|17β-E2]].<ref name=":0">{{Cite journal |last1=Getoff |first1=Nikola |last2=Gerschpacher |first2=Marion |last3=Hartmann |first3=Johannes |last4=Huber |first4=Johannes C. |last5=Schittl |first5=Heike |last6=Quint |first6=Ruth Maria |date=2010-01-21 |title=The 4-hydroxyestrone: Electron emission, formation of secondary metabolites and mechanisms of carcinogenesis |journal=Journal of Photochemistry and Photobiology B: Biology |volume=98 |issue=1 |pages=20–24 |doi=10.1016/j.jphotobiol.2009.10.003 |issn=1011-1344 |pmc=2955241 |pmid=19926488}}</ref><ref name=":1">{{Cite journal |last1=Miao |first1=Suyu |last2=Yang |first2=Fengming |last3=Wang |first3=Ying |last4=Shao |first4=Chuchu |last5=Zava |first5=David T. |last6=Ding |first6=Qiang |last7=Shi |first7=Yuenian Eric |date=2019 |title=4-Hydroxy estrogen metabolite, causing genomic instability by attenuating the function of spindle-assembly checkpoint, can serve as a biomarker for breast cancer |journal=American Journal of Translational Research |volume=11 |issue=8 |pages=4992–5007 |issn=1943-8141 |pmc=6731443 |pmid=31497216}}</ref><ref name=":2">{{Cite journal |last1=Wang |first1=Hongge |last2=Hou |first2=Ming-Jie |last3=Liao |first3=Lixi |last4=Li |first4=Peng |last5=Chen |first5=Tongxiang |last6=Wang |first6=Pan |last7=Zhu |first7=Bao Ting |date=2024-04-16 |title=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 |journal=Biochemistry |volume=63 |issue=8 |pages=984–999 |doi=10.1021/acs.biochem.3c00261 |issn=0006-2960 |pmc=11025120 |pmid=38569593}}</ref>

== Biochemical Studies Related to 4-OHE1's Role as a Carcinogen and Neuroestrogen ==
4-OHE1 behaves similarly to [[Estradiol|17β-E2]] in [[electron emission]] processes. A study on [[electron emission]] of [[Estradiol|17β-E2]] demonstrated that 4-OHE1, as a secondary metabolite, can emit electrons in a similar mechanism post-[[Ultraviolet|UV]] excitation.<ref name=":0" /> Additionally, studies related to the [[central nervous system]] (CNS) observed that the hydroxylation process in [[Estradiol|17β-E2]] also occurs in cerebral enzymes.<ref name=":3" />

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 [[List of chemotherapeutic agents|chemotherepeutic]] resistance, against [[docetaxel]].<ref name=":1" />

In 2020, studies comparing [[Estradiol|17β-E2]] and hydroxy esterone revealed that 4-OHE1 contributes to the [[cytoplasm]]ic [[Chromosomal translocation|translocation]] of [[p53]], a key tumor supressor protein, contributing to its role in cellular responses from [[Stress (biology)|stress]] and damage.<ref name=":3" />

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]] [[Enzyme inhibitor|inhibitor]], a form of programmed cell death associated with cancer cell survival. Specifically, 4-OHE1 inhibits the [[Protein disulfide-isomerase|protein disulfide isomerase]] (PDI), which is involved in the [[ferroptosis]] of specific breast cancer cells. By forming two [[hydrogen bond]]s with a crucial [[histidine]] residue in [[Protein disulfide-isomerase|PDI]], 4-OHE1 prevents [[cell death]] in these cells. Additionally, the 4-OHE1-[[Protein disulfide-isomerase|PDI]] complex displays greater [[binding affinity]] but lower [[binding energy]] than a [[Estradiol|17β-E2]]-[[Protein disulfide-isomerase|PDI]] complex<ref name=":2" />

Earlier research has indicated that natural estrogens can help protect the brain from oxidative harm. This current study aims to explore how different estrogen metabolites produced by the body can guard against neurotoxicity caused by oxidation, both in lab settings and in live subjects. When testing 25 endogenous estrogen metabolites using mouse hippocampal neuron cells, researchers found that 4-hydroxyestrone—a metabolite of estrone with minimal estrogen-like activity—was surprisingly effective at shielding neurons from oxidative stress. It even outperformed 17β-estradiol! Likewise, when looking at rats exposed to kanic acid-induced damage in their hippocampus, 4-hydroxyestrone showed a stronger protective effect compared to 17β-estradiol as well. The way it works is linked to an increase in p53 movement within cells due to SIRT1-mediated deacetylation of p53. Further examination of brain enzymes revealed that converting estrogens into their hydroxylated forms is a key metabolic route within the central nervous system. All these findings point towards 4-hydroxyestrone being a powerful neuroestrogen capable of providing significant protection against neuronal oxidative injury.<ref>{{cite journal |last1=Choi |first1=Hye Joung |last2=Lee |first2=Anthony J. |last3=Kang |first3=Ki Sung |last4=Song |first4=Ji Hoon |last5=Zhu |first5=Bao Ting |title=4-Hydroxyestrone, an Endogenous Estrogen Metabolite, Can Strongly Protect Neuronal Cells Against Oxidative Damage |journal=Scientific Reports |date=29 April 2020 |volume=10 |issue=1 |doi=10.1038/s41598-020-62984-y|pmc=7190733 }}</ref>

Hydroxyestrone (4-OHE1), a well-known cancer-causing metabolite that comes from 17β-estradiol (17β-E2), was picked as the subject for these studies. The goal was to dig deeper into how it kicks off cancer development. It turns out that when 4-OHE1 is energized in its singlet state using monochromatic UV light at a wavelength of 254 nm within polar environments like a water-ethanol mix (40:60 vol%), it can actually release electrons (e aq -).<ref>{{cite journal |last1=Getoff |first1=Nikola |last2=Gerschpacher |first2=Marion |last3=Hartmann |first3=Johannes |last4=Huber |first4=Johannes C. |last5=Schittl |first5=Heike |last6=Quint |first6=Ruth Maria |title=The 4-hydroxyestrone: Electron emission, formation of secondary metabolites and mechanisms of carcinogenesis |journal=Journal of Photochemistry and Photobiology B: Biology |date=January 2010 |volume=98 |issue=1 |pages=20–24 |doi=10.1016/j.jphotobiol.2009.10.003|pmc=2955241 }}</ref>

== See also ==
* [[Estrogen conjugate]]
* [[Lipoidal estradiol]]
* [[Estradiol|17β-estradiol]] (another name for [[Estradiol]] or E2)

== References ==
{{Reflist}}

==External links==
* [http://www.hmdb.ca/metabolites/HMDB05895 Metabocard for 4-Hydroxyestrone - Human Metabolome Database]

{{Endogenous steroids}}
{{Estrogen receptor modulators}}

{{DEFAULTSORT:Hydroxyestrone, 4-}}
[[Category:Catechols]]
[[Category:Estranes]]
[[Category:Estrogens]]
[[Category:Human metabolites]]
[[Category:Hydroxyketones]]