Editing Gossypol

{{Distinguish|Gossypetin}}
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| verifiedrevid = 443848830
| ImageFile1 = Gossypol.png
| ImageSize1 = 
| ImageFile2 = Gossypol_(structure).png
| ImageSize2 = 
| PIN = 1,1′,6,6′,7,7′-Hexahydroxy-3,3′-dimethyl-5,5′-di(propan-2-yl)[2,2′-binaphthalene]-8,8′-dicarbaldehyde
| OtherNames =
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 4204
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| ChemSpiderID = 3383
| InChIKey = QBKSWRVVCFFDOT-UHFFFAOYAH
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 51483
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C30H30O8/c1-11(2)19-15-7-13(5)21(27(35)23(15)17(9-31)25(33)29(19)37)22-14(6)8-16-20(12(3)4)30(38)26(34)18(10-32)24(16)28(22)36/h7-12,33-38H,1-6H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = QBKSWRVVCFFDOT-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 303-45-7
| PubChem = 3503
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C07667
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = KAV15B369O
| DrugBank=DB13044
| SMILES = CC(C)c1c(O)c(O)c(C=O)c2c1cc(C)c(c2O)-c(c3O)c(C)cc4c3c(C=O)c(O)c(O)c4C(C)C
| InChI = 1/C30H30O8/c1-11(2)19-15-7-13(5)21(27(35)23(15)17(9-31)25(33)29(19)37)22-14(6)8-16-20(12(3)4)30(38)26(34)18(10-32)24(16)28(22)36/h7-12,33-38H,1-6H3
}}
|Section2={{Chembox Properties
| C=30
| H=30
| O=8
| Appearance = Brown solid
| Density = 1.4 g/mL
| MeltingPtC = 177 to 182
| MeltingPt_notes = (decomposes)
| BoilingPtC =707
| Solubility =
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|Section3={{Chembox Related
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|Section7={{Chembox Hazards
| GHSPictograms = {{GHS07}}
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| HPhrases = {{H-phrases|351}}
| PPhrases = {{P-phrases|201|202|281|308+313|405|501}}
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}}

'''Gossypol''' ({{IPAc-en|ˈ|ɡ|ɒ|s|ə|p|ɒ|l}}) is a [[natural phenol]] derived from the cotton plant (genus ''[[Gossypium]]''). Gossypol is a phenolic [[aldehyde]] that permeates cells and acts as an [[Enzyme inhibitor|inhibitor]] for several [[dehydrogenase]] [[enzyme]]s. It is a yellow [[pigment]]. The structure exhibits [[Atropisomer|atropisomerism]], with the two [[enantiomer]]s having different biochemical properties.<ref>{{cite journal |journal= Journal of Molecular Structure: THEOCHEM |volume= 730 |year= 2005 |pages= 51–58 |title= Conformational analysis of gossypol and its derivatives by molecular mechanics |first1= Chase L. |last1= Beise |first2= Michael K. |last2= Dowd |first3= Peter J. |last3= Reilly |issue= 1–3 |doi= 10.1016/j.theochem.2005.05.010 |url= https://lib.dr.iastate.edu/cbe_pubs/26 }}</ref>

Among other applications, it has been tested as a [[male oral contraceptive]] in [[China]]. In addition to its putative contraceptive properties, gossypol has also long been known to possess [[antimalarial]] properties.<ref>{{Cite journal|last=Dodou|first=Kalliopi|date=2005-10-28|title=Investigations on gossypol: past and present developments|journal=Expert Opinion on Investigational Drugs|language=en|volume=14|issue=11|pages=1419–1434|doi=10.1517/13543784.14.11.1419|pmid=16255680|s2cid=32120983|issn=1354-3784}}</ref>

== History ==
Utilization of cotton-seed oil in the 19th century was complicated by the fact that it stained everything. In 1882-1883 James Longmore from Liverpool took several patents on separating the colorant by partial [[saponification]] of the oil,<ref>{{Cite book |url=https://books.google.com/books?id=wsQ6AQAAMAAJ&pg=PA65 |title=Patents for Inventions. Abridgments of Specifications |date=1893 |language=en |last1=Patent Office |first1=Great Britain }}</ref><ref>{{Cite book |url=https://books.google.com/books?id=b5ZQAQAAIAAJ&pg=PA67 |title=Reports of Patent, Design, and Trade Mark Cases |date=1892 |publisher=Published at the Patent Office Sales Branch |language=en}}</ref> and in 1886 he presented his findings to the local section of the [[Society of Chemical Industry]].<ref>{{Cite book |url=https://books.google.com/books?id=vCTzAAAAMAAJ&pg=PA200 |title=Journal of the Society of Chemical Industry |date=1886 |publisher=Society of Chemical Industry. |language=en}}</ref> He is often considered the discoverer of gossypol, even though he only isolated it in crude form.<ref>{{Citation |last1=Wang |first1=Xi |title=Chapter 6 Gossypol-A Polyphenolic Compound from Cotton Plant |date=2009 |volume=58 |pages=215–263 |url=https://www.sciencedirect.com/science/article/abs/pii/S1043452609580060 |access-date=2024-11-24 |series=Advances in Food and Nutrition Research |publisher=Academic Press |last2=Howell |first2=Cheryl Page |last3=Chen |first3=Feng |last4=Yin |first4=Juanjuan |last5=Jiang |first5=Yueming|doi=10.1016/S1043-4526(09)58006-0 |pmid=19878861 |isbn=978-0-12-374441-8 |url-access=subscription }}</ref>

The name was coined in 1899 by [[Leon Marchlewski]], who first purified the compound and studied some of its chemical properties.<ref>{{Cite journal |last=Marchlewski |first=L. |date=1899-12-07 |title=Gossypol, ein Bestandtheil der Baumwollsamen |url=https://books.google.com/books?id=kwAwAAAAIAAJ&pg=RA1-PA84 |journal=Journal für Praktische Chemie |language=en |volume=60 |issue=1 |pages=84–90 |doi=10.1002/prac.18990600108 |issn=0021-8383}}</ref> W. A. Withers and F. E. Carruth first attributed the toxic properties of the cotton seed (known since the 19th c.) to gossypol in 1915,<ref>{{Cite journal |last1=Withers |first1=W. A. |last2=Carruth |first2=F. E. |date=1915-02-26 |title=Gossypol—A Toxic Substance in Cottonseed. A Preliminary Note |url=https://www.science.org/doi/10.1126/science.41.1052.324.b |journal=Science |language=en |volume=41 |issue=1052 |pages=324 |doi=10.1126/science.41.1052.324.b |issn=0036-8075|url-access=subscription }}</ref> and its chemical formula was established in 1927 by Earl Perry Clark (1892-1943).<ref>{{Cite journal |last=Clark |first=E. P. |date=1927-12-01 |title=STUDIES ON GOSSYPOL: I. THE PREPARATION, PURIFICATION, AND SOME OF THE PROPERTIES OF GOSSYPOL, THE TOXIC PRINCIPLE OF COTTONSEED |journal=Journal of Biological Chemistry |volume=75 |issue=3 |pages=725–739 |doi=10.1016/S0021-9258(18)84141-2 |issn=0021-9258|doi-access=free }}</ref>

==Biosynthesis==
Gossypol is a [[terpenoid]] [[aldehyde]] which is formed metabolically through [[Acetic acid|acetate]] via the [[isoprenoid pathway]].<ref>{{cite journal|last1=Burgos |first1=M. |last2=Ito |first2=S. |last3=Segal |first3=J. S. |last4=Tran |first4=T. P. |title=Effect of Gossypol on Ultrastructure of Spisula Sperm|journal=The Biological Bulletin |year=1997|volume=193|issue=2|pages=228–229|doi=10.1086/BBLv193n2p228|pmid=28575607 }}</ref> The [[sesquiterpene]] dimer undergoes a radical coupling reaction to form gossypol.<ref>{{cite journal|last1=Heinstein |first1=P. F. |last2=Herman |first2=L. D. |last3=Tove |first3=B. S. |last4=Smith |first4=H. F. |title=Biosynthesis of Gossypol|journal= Journal of Biological Chemistry |year=1970|volume=245|pages=4658–4665|pmid=4318479|issue=18|doi=10.1016/S0021-9258(18)62845-5 |doi-access=free }}</ref> The biosynthesis begins when [[geranyl pyrophosphate]] (GPP) and [[isopentenyl pyrophosphate]] (IPP) are combined to make the [[sesquiterpene]] precursor [[farnesyl diphosphate]] (FPP). The cadinyl cation ('''1''') is oxidized to '''2''' by [[Delta-cadinene synthase|(+)-δ-cadinene synthase]]. The [[cadinene|(+)-δ-cadinene]] ('''2''') is involved in making the basic aromatic sesquiterpene unit, homigossypol, by oxidation, which generates the '''3''' (8-hydroxy-δ-cadinene) with the help of (+)-δ-cadinene 8-hyroxylase. Compound '''3''' goes through various oxidative processes to make '''4''' (deoxyhemigossypol), which is oxidized by one electron into hemigossypol ('''5''', '''6''', '''7''') and then undergoes a phenolic [[oxidative coupling]], [[Arene substitution pattern#Ortho, meta, and para substitution|''ortho'']] to the phenol groups, to form gossypol ('''8''').<ref name="autogenerated1">{{cite book | author = Dewick, P. M. | url = https://www.dmt-nexus.com/doc/Medicinal%20Natural%20Products%20-%20A%20Biosynthetic%20Approach.pdf | title = Medicinal Natural Product: A Biosynthetic Approach | edition = 3rd | date = 2008 | isbn = 978-0-470-74167-2 }}{{Dead link|date=January 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The coupling is catalyzed by a [[hydrogen peroxide]]-dependent [[peroxidase]] enzyme, which results in the final product.<ref name="autogenerated1"/>

:[[File:Gossypol biosyn.jpg|500 px]]

==Research==

===Contraception===
A 1929 investigation in [[Jiangxi]] showed correlation between low [[fertility]] in males and use of crude [[cottonseed oil]] for cooking. The compound causing the contraceptive effect was determined to be gossypol.<ref name=andrology>{{cite journal | last1=YU | first1=ZONG-HAN | last2=CHAN | first2=HSIAO CHANG | title=Gossypol as a male antifertility agent - why studies should have been continued | journal=International Journal of Andrology | volume=21 | issue=1 | year=1998 | issn=0105-6263 | doi=10.1046/j.1365-2605.1998.00091.x|doi-access=free| pages=2–7| pmid=9639145 }}</ref>
In the 1970s, the [[Government of the People's Republic of China|Chinese government]] began researching the use of gossypol as a [[contraceptive]]. Their studies involved over 10,000 subjects, and continued for over a decade. They concluded that gossypol provided reliable contraception, could be taken orally as a tablet, and did not upset men's balance of hormones.

However, gossypol also had serious flaws. The studies also discovered an abnormally high rate (0.75%) of [[hypokalemia]] (low blood [[potassium]] levels) among subjects.<ref name=andrology/><ref name="Gossypol">{{cite web|url=http://malecontraceptives.org/methods/gossypol.php|title=Gossypol|website=Malecontraceptives.org|date=2011-07-27|archive-date=2013-05-18|archive-url=https://web.archive.org/web/20130518114513/http://malecontraceptives.org/methods/gossypol.php|url-status=dead}}</ref> Hypokalemia causes symptoms of [[fatigue (medical)|fatigue]], muscle weakness, and at its most extreme, [[paralysis]]. In addition, about 7% of subjects reported effects on their [[digestive system]]s,<ref name=andrology/> about 12% had increased fatigue, some subjects experienced impotence or reduced libido, and 9.9% became irreversibly infertile, apparently associated with longer treatment and greater total dose of gossypol.<ref name=andrology/> Most subjects recovered after stopping treatment and taking potassium supplements. The same study showed taking potassium supplements during gossypol treatment did not prevent hypokalemia in [[primate]]s.<ref name="Gossypol"/> The potassium deficiency may also be a result of the Chinese diet or genetic predisposition.<ref name="Gossypol"/>

In the mid-1990s, the Brazilian pharmaceutical company Hebron announced plans to market a low-dose gossypol pill called Nofertil, but the pill never came to market. Its release was indefinitely postponed due to unacceptably high rates of permanent infertility.{{citation needed|date=November 2012}} 5% to 25% of the men remained [[azoospermic]] up to a year after stopping treatment.<ref name="Gossypol"/> 

Researchers have suggested gossypol might make a good noninvasive alternative to surgical [[vasectomy]].<ref>{{cite journal|journal=Contraception| last=Coutinho |first=F. M.| title = Gossypol: a contraceptive for men| year = 2002| volume = 65| issue = 4| pages = 259–263| pmid= 12020773| doi = 10.1016/S0010-7824(02)00294-9}}</ref>

In 1986, in conjunction with the Chinese Ministry of Public Health and the [[Rockefeller Foundation]], the [[World Health Organization]] formalized a decision to discontinue research into gossypol as a male contraceptive drug.<ref name="IJA199804">{{cite journal |journal=International Journal of Andrology |issn=0105-6263 |title=Gossypol: Reasons for its failure to be accepted as a safe, reversible male antifertility drug |publication-date=April 1998 |pages=8–12 |given1=G. M. H. |surname1=Waites |given2=C. |surname2=Wang |given3=P. D. |surname3=Griffin |year=1998 |department=Point of View Review |volume=21 |number=1 |doi=10.1046/j.1365-2605.1998.00092.x|pmid=9639146 |doi-access=free }}</ref> In addition to the other side effects, the WHO researchers were concerned about gossypol's toxicity: the {{LD50}} in primates is less than 10 times the contraceptive dose,<ref name="Gossypol"/> creating a small [[therapeutic window]]. This report effectively ended further studies of gossypol as a temporary contraceptive, but research into using it as an alternative to vasectomy continues in Austria, Brazil, Chile, China, the Dominican Republic, and Nigeria.

==Toxicity ==
Food and animal agricultural industries must manage cotton-derivative product levels to avoid toxicity. For example, only [[ruminant]] [[microflora]] can digest gossypol, and then only to a certain level, and [[cottonseed oil]] must be refined. [[genetic engineering|Genetically engineered]] cotton plants that contain little gossypol in the seed may still contain the compound in the stems and leaves.<ref>{{Cite web|url=https://today.tamu.edu/2018/10/16/edible-cottonseed-research-at-texas-am-receives-usda-approval/|title=Seeding Hope for Millions|date=2018-10-16|website=Texas A&M Today|language=en-US|access-date=2019-10-07}}</ref>

==References==
{{reflist|30em}}

==External links==
* {{Commons category inline|Gossypol}}

[[Category:Contraception for males]]
[[Category:Plant toxins]]
[[Category:Suspected embryotoxins]]
[[Category:Dimers (chemistry)]]
[[Category:Aromatic aldehydes]]
[[Category:Naphthols]]
[[Category:Catechols]]
[[Category:Isopropyl compounds]]
[[Category:Cotton]]
[[Category:3-Hydroxypropenals]]
[[Category:Polyols]]
[[Category:Aldehyde dehydrogenase inhibitors]]