Coumestrolのソースを表示

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'''Coumestrol''' is a natural [[organic compound]] in the class of [[phytochemical]]s known as [[coumestan]]s. Coumestrol was first identified as a compound with estrogenic properties by E. M. Bickoff in ladino [[clover]] and [[alfalfa]] in 1957.<ref>{{cite journal |title=Coumestrol, a New Estrogen Isolated from Forage Crops |author1=E. M. Bickoff |author2=A. N. Booth |author3=R. L. Lyman |author4=A. L. Livingston |author5=C. R. Thompson |author6=F. Deeds |journal=Science |year=1957 |volume=126 |pages=969–970 |doi=10.1126/science.126.3280.969-a |pmid=13486041 |issue=3280|bibcode=1957Sci...126..969B }}</ref>  It has garnered research interest because of its estrogenic activity and prevalence in some foods, including [[soybean]]s, [[brussels sprout]]s, [[spinach]] and a variety of [[legume]]s. The highest concentrations of coumestrol are found in [[clover]], Kala Chana (a type of [[chick pea]]), and [[Alfalfa|Alfalfa sprouts]].<ref name =Bhagwat>{{cite book|last1=Bhagwat|first1=Seema|last2=Haytowitz|first2=David|last3=Holden|first3=Joanne|title=USDA Database for the Isoflavone Content of Selected Foods|date=September 2008|publisher=U.S. Department of Agriculture|location=Beltsville, Maryland|edition=Release 2.0|url=http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/isoflav/Isoflav_R2.pdf|access-date=10 March 2015}}</ref>

Coumestrol is a [[phytoestrogen]], mimicking the [[biological activity]] of [[estrogen]]s. Phytoestrogens are able to pass through cell membranes due to their low molecular weight and stable structure, and they are able to interact with the enzymes and receptors of cells.<ref name=ososki>{{cite journal|last1=Ososki|first1=Andreana L.|last2=Kennelly|first2=Edward J.|title=Phytoestrogens: a Review of the Present State of Research|journal=Phytotherapy Research|date=2003|volume=17|issue=8|pages=845–869|pmid=13680814|doi=10.1002/ptr.1364|s2cid=32550431}}<!--|access-date=16 April 2015--></ref> Coumestrol binds to the [[ERα]] and [[ERβ]] with similar [[affinity (pharmacology)|affinity]] to that of [[estradiol]] (94% and 185% of the [[relative binding affinity]] of estradiol at the 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> although the estrogenic activity of coumestrol at both receptors is much less than that of estradiol.<ref>{{cite journal |vauthors=Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA | title=Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta | journal=Endocrinology  | volume=139 | issue=10 | year=1998 | pages=4252–4263  | url = http://endo.endojournals.org/cgi/content/full/139/10/4252 | pmid=9751507 | doi=10.1210/endo.139.10.6216| doi-access= }}</ref> In any case, coumestrol has estrogenic activity that is 30 to 100 times greater than that of isoflavones.<ref>{{Cite journal|last=Konar|first=Nevzat|title=Non-isoflavone phytoestrogenic compound contents of various legumes|journal=European Food Research and Technology|language=en|volume=236|issue=3|pages=523–530|doi=10.1007/s00217-013-1914-0|issn=1438-2377|year=2013|s2cid=85373016}}</ref>

The chemical shape of coumestrol orients its two [[hydroxyl|hydroxy]] groups in the same position as the two hydroxy groups in estradiol, allowing it to [[enzyme inhibition|inhibit]] the activity of [[aromatase]] and [[3α-hydroxysteroid dehydrogenase]].<ref>{{cite journal|vauthors=Blomquist CH, Lima PH, Hotchkiss JR |title=Inhibition of 3a-hydroxysteoid dehydogenase (3a-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C18-, C19- and C21 hydroxysteroids and ketosteroids|journal=Steroids|year=2005|volume=70|issue=8|pages=507–514|doi=10.1016/j.steroids.2005.01.004|pmid=15894034|s2cid=54388469}}</ref> These enzymes are involved in the biosynthesis of [[steroid]] hormones, and inhibition of these enzymes results in the interference with hormone [[metabolism]].<ref name="Amin">{{cite journal|author1=Amr Amin |author2=Michael Buratovich |title=The Anti-Cancer Charm of Flavonoids: A Cup-of-Tea Will Do!|journal=Recent Patents on Anti-Cancer Drug Discovery|year=2007|issue=2|pages=109–117|doi=10.2174/157489207780832414|volume=2|pmid=18221056}}</ref>

==Natural sources and dietary intake==
Levels of coumestrol within individual plants of the same species are variable. Studies of coumestrol levels in alfalfa suggest that there may be a positive correlation between coumestrol production and infection of the plant by [[viruses]], [[bacteria]], and [[fungi]]. Higher levels of coumestrol are also found in plants which had been damaged by [[aphids]]. Further study is required to fully explain the cause of the correlation between damage, infection, and coumestrol levels.<ref name= USDA >{{cite book|last1=United States Department of Agriculture|title=Studies on the Chemical and Biological Properties of Coumestrol and Related Compounds|date=2003|publisher=US Government Printing Office|pages=47–67|url=http://naldc.nal.usda.gov/download/CAT70293436/PDF|access-date=2015-03-17|archive-date=2015-04-02|archive-url=https://web.archive.org/web/20150402093932/http://naldc.nal.usda.gov/download/CAT70293436/PDF|url-status=dead}}</ref>

According to the [[United States Department of Agriculture]] and [[Iowa State University]] database on [[isoflavanes]] and coumestrol, coumestrol is found in the following food items:
{| class="wikitable"
|-
! Food Item!! Coumestrol Level (mg/100g)
|-
| Large, dry [[Lima beans]] || 0.14
|-
| Raw [[Pinto Bean]]s || 1.80
|-
| Dry Kala Chana || 6.13 
|-
| [[Alfalfa]] Sprouts || 1.60
|-
| Raw [[Clover]] Sprouts || 14.08
|-
| Soy Sprouts || 0.34
|-
| Mature [[Soybeans|Soy Beans]] || 0.02
|-
| Unfortified Original and Vanilla [[Soy milk]] || 0.81
|-
| Firm [[Tofu]] Prepared with [[Calcium Sulfate]] and [[Magnesium Chloride]]|| 0.12
|-
| Doughnuts with Soy Flour of Protein || 0.24
|}<ref name= "Bhagwat"/><ref>{{cite web |title=USDA-Iowa State University Database on the Isoflavone Content of Foods |url=https://www.ars.usda.gov/ARSUserFiles/80400525/data/isoflav/isoflav1-4.pdf |access-date=10 March 2022}}</ref>

Based on extrapolation from studies done on animals, the maximum tolerable daily intake of coumestrol for human beings has been estimated at 22 μg per kg of body mass. This was calculated by extrapolating from the lowest level at which adverse effects were seen in animals. Although due to the variability of the human diet, the exact amount of coumestrol the average person consumes has not been calculated, studies of phytoestrogen intake suggest that most human diets result in a negligible intake of coumestrol relative to the maximum tolerable daily intake.<ref name= Shaw>{{cite book|last1=Shaw|first1=Ian|title=Endocrine-disrupting chemicals in food|date=March 2009|publisher=Woodhead Publishing Limited|location=Cambridge|isbn=9781845695743}}</ref>

==Biological effects on mammals==
{{Missing information|section|numbers for activity on receptors (rel. affinity, rel. agnoism), including aforementioned ERa/b, new PXR ({{PMID|18096694}}), and a somewhat surprising MAO-A ({{PMID|36145197}})|date=October 2022}}
Because coumestrol is an estrogen mimic, it is an [[endocrine disruptor]] with the potential to affect all organ systems that are regulated hormonally via estrogens.

===Nervous system===
Coumestrol and other phytoestrogens have been shown to have an effect on sexual behavior in rats by antagonizing the action of estrogen within the brain; male rats that nursed from females with coumestrol in their diets were both less likely to mount a female rat and less likely to ejaculate, despite producing normal levels of [[testosterone]]. Exposure produced similar decreases of sexual behavior in female rats, as a result of the disruption of estrogen dependent gene expression in the brain. Effects were seen in three areas of the [[hypothalamus]], the [[ventromedial nucleus]], the [[paraventricular nucleus]], and the [[Preoptic area|medial preoptic area]], all of which play a role in sexual behavior and sexual activity.<ref name=Whitten>{{cite journal|last1=Whitten|first1=Patricia|last2=Patisaul|first2=Heather|last3=Young|first3=Larry|title=Neurobehavioural actions of coumestrol and related isoflavonoids in rodents|journal=Neurotoxicology and Teratology|date=2002|volume=24|issue=1|pages=47–54|doi=10.1016/s0892-0362(01)00192-1|pmid=11836071}}</ref><ref name=Naz>{{cite book|last1=Naz|first1=Rajesh K.|title=Endocrine disruptors : effects on male and female reproductive systems|date=2005|publisher=CRC Press|location=Boca Raton|isbn=9780849322815|edition=2nd}}</ref> Female rats that were exposed to coumestrol [[neonatal]]ly did not adopt the [[Lordosis behavior|lordosis]] position as much as those that were not exposed to coumestrol.<ref name=Jefferson>{{cite journal|last1=Jefferson|first1=WN|last2=Patisaul|first2=HB|last3=Williams|first3=CJ|title=Reproductive consequences of developmental phytoestrogen exposure|journal=Reproduction|date=March 2012|volume=143|issue=3|pages=247–60|pmid=22223686|doi=10.1530/rep-11-0369|pmc=3443604}}<!--|access-date=28 March 2015--></ref>

===Reproductive system===
Coumestrol has been shown to accelerate the onset of puberty in mice.<ref name= "Shaw"/> Exposure to coumestrol immediately after birth resulted in an initial increase in uterine weight. However, continued exposure inhibited the growth of the [[uterus]] and decreased levels of [[estrogen receptors]] within uterine tissue. The rats also showed altered vaginal development including [[cornification]] and [[metaplasia]] of vaginal tissue, and delayed opening of the vagina.<ref name="Naz"/> When [[neonatal]] female mice were treated with coumestrol, similar reproductive irregularities occurred, and at 22 months old, atypical [[collagen]] distribution was observed in the uterine wall.<ref name=Jefferson /> When 2 day old male [[Wistar rats]] are injected with coumestrol daily, they exhibit a decrease in size in the [[Lumen (anatomy)|lumens]] of their [[seminiferous tubules]] and germ cells go through increased rates of [[apoptosis]]. When bulls graze on pastures containing coumestrol, metaplasia occurs in the [[prostate]] and [[bulbourethral]] glands, and sperm maturation is suppressed. Female cows that consumed alfalfa experienced lower pregnancy rates and spontaneous abortions, as well as abnormal estrogen levels during pregnancy.<ref name=Perez-Rivero>{{cite journal|last1=Perez-Rivero|first1=Juan|last2=Aguilar-Setien|first2=Alvaro|last3=Martinez-Maya|first3=Jos|last4=Perez-Martino|first4=Mario|last5=Serrano|first5=Hector|title=Phytoestrogens and Effect of Consumption and Their Effects in Different Organs and Systems of Domestic Animals|journal=Agricultura Tecnica|volume=67 | issue = 3 }}</ref> A high coumestrol diet has also been shown to induce early development of the [[vulva]] and [[udder]] of female lambs.  In addition to these anatomical abnormalities, exposure to coumestrol has also been shown to alter the [[estrus]] cycle of a number of animals, including cows and sheep, resulting in lower rates of fertility.<ref name= "USDA"/>

===Skeletal system===
Coumestrol has been shown to decrease [[bone resorption]] and promote the [[mineralization of bone]] ''in vitro'' and ''in vivo''; daily injections of coumestrol were shown to reduce bone loss in rats who had undergone an [[ovariectomy]].<ref name= "Naz"/>

===Genotoxicity===
{{main|Genotoxicity}}

Coumestrol has been shown to have [[clastogen]]ic properties at a certain concentration.{{specify|date=January 2018}}. Studies have shown that coumestrol is a [[mutagen]] and induces formation of [[Micronucleus test|micronuclei]] in hamster cells of the V79 cell line as well as human [[lymphoblastoid]] cells in a dose-dependent manner. Exposure to coumestrol also causes single stranded breaks in hamster DNA, compromising genome stability.<ref>{{cite journal|last1=Stopper|first1=H|last2=Schmitt|first2=E|last3=Kobras|first3=K|title=Genotoxicity of phytoestrogens|journal=Mutation Research|date=1 July 2005|volume=574|issue=1–2|pages=139–55|pmid=15914213|doi=10.1016/j.mrfmmm.2005.01.029}}</ref>

===Metabolism===
Studies have shown that coumestrol has beneficial properties on carbohydrate metabolism in [[Ovariectomized rat|ovariectomized]] rats, decreasing glycogen levels in skeletal muscle. There is also data indicating that coumestrol lowers plasma cholesterol levels in chicks. These results point to a possibility of coumestrol having a positive role to play against human obesity and diabetes in the future.<ref name=Preedy>{{cite book|editor-last1=Preedy|editor-first1=Victor R.|title=Isoflavones chemistry, analysis, function and effects|url=https://archive.org/details/isoflavoneschemi00pree|url-access=limited|date=2013|publisher=Royal Society of Chemistry|location=Cambridge, U.K.|isbn=978-1-84973-509-4|pages=[https://archive.org/details/isoflavoneschemi00pree/page/n544 518]–526}}</ref>

===Menopause===
Coumestrol and other phytoestrogens are sometimes used as a substitute for hormone therapy in the treatment of [[menopausal symptoms]] such as hot flashes and night sweats. However, studies have indicated that phytoestrogen-enriched foods and supplements are not necessarily effective against these symptoms.<ref>{{cite journal|last1=Lethaby|first1=A|last2=Marjoribanks|first2=J|last3=Kronenberg|first3=F|last4=Roberts|first4=H|last5=Eden|first5=J|last6=Brown|first6=J|title=Phytoestrogens for menopausal vasomotor symptoms|journal=The Cochrane Database of Systematic Reviews|date=10 December 2013|volume=2013|issue=12|pages=CD001395|pmid=24323914|doi=10.1002/14651858.CD001395.pub4|pmc=10247921}}</ref> In addition, studies indicate that coumestrol and other phytoestrogens have an antiestrogenic effect in the brain and, as a result, do not produce the mental health benefits which are seen in estrogen replacement therapy.<ref name = "Whitten"/>

===Breast cancer===
Coumestrol and other phytoestrogens have also been investigated as a possible substitute for hormone therapy and [[chemotherapy]] in [[breast cancer]] patients. The results of various studies regarding the use of phytoestrogens in treating breast cancer have been somewhat contradictory and ambiguous, and as a result, researchers cannot clearly define phytoestrogens like coumestrol as being [[chemoprotective agent]]s or potentially having negative effects, such as inducing further growth of existing breast cancer tumors by activating [[Estrogen receptor alpha|ERα receptors]].<ref>{{cite journal|last1=Mense|first1=SM|last2=Hei|first2=TK|last3=Ganju|first3=RK|last4=Bhat|first4=HK|title=Phytoestrogens and breast cancer prevention: possible mechanisms of action|journal=Environmental Health Perspectives|date=April 2008|volume=116|issue=4|pages=426–33|pmid=18414622|doi=10.1289/ehp.10538|pmc=2291001}}</ref>
Researchers at [[Georgetown University Medical Center]] have investigated this matter and concluded that phytoestrogens may be used as an effective treatment for breast cancer because of their [[apoptotic]] properties, but that it is only safe to do so after menopause, when women have a much lower level of estrogen in their bodies, or when used conjunctively with anti-estrogen therapies.<ref>{{cite journal|last1=Obiorah|first1=IE|last2=Fan|first2=P|last3=Jordan|first3=VC|title=Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state|journal=Cancer Prevention Research (Philadelphia, Pa.)|date=September 2014|volume=7|issue=9|pages=939–49|pmid=24894196|doi=10.1158/1940-6207.capr-14-0061|doi-access=free}}</ref>

==Current and future research==
Most research on the biological effects of coumestrol has been conducted on animals because of ethical concerns. There is a need for more human studies to better understand potential human health impacts due to exposure.<ref name= "Preedy"/>
In addition, further research is required to fully understand the biosynthesis pathway of coumestrol, although it is believed to be similar to that of [[flavones]] and isoflavones. Further research is required to understand the exact nature of the relationship between the levels of coumestrol in a plant and the plant's response to pathogens.<ref name= "USDA"/>

==References==
{{Reflist|2}}

==Further reading==
* {{cite journal|author1=Kshirsagar, U.A. |author2=Parnes, R. |author3=Goldshtein, H. |author4=Ofir, R. |author5=Zarivach, R. |author6=Pappo, D. |title=Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators|journal=Chem. Eur. J.|year=2013|volume=19|issue=40|pages=13575–13583|doi=10.1002/chem.201300389|pmid=23946113}}

{{Phytoestrogens}}
{{Estrogen receptor modulators}}

[[Category:3α-Hydroxysteroid dehydrogenase inhibitors]]
[[Category:Aromatase inhibitors]]
[[Category:Coumestans]]
[[Category:Phytoestrogens]]
<!-- [[Category:Benzofuranochromenes]] -->
[[Category:Selective ERβ agonists]]
[[Category:Hydroxyarenes]]
[[Category:Diols]]