gossypol

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,{{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 }}{{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}} and in 1886 he presented his findings to the local section of the Society of Chemical Industry.{{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}} He is often considered the discoverer of gossypol, even though he only isolated it in crude form.{{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 }}

The name was coined in 1899 by Leon Marchlewski, who first purified the compound and studied some of its chemical properties.{{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}} 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,{{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 }} and its chemical formula was established in 1927 by Earl Perry Clark (1892-1943).{{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 }}

Gossypol is a terpenoid aldehyde which is formed metabolically through acetate via the isoprenoid pathway.{{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 }} The sesquiterpene dimer undergoes a radical coupling reaction to form gossypol.{{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 }} 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 (+)-δ-cadinene synthase. The (+)-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, ortho to the phenol groups, to form gossypol (8).{{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 }} The coupling is catalyzed by a hydrogen peroxide-dependent peroxidase enzyme, which results in the final product.

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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.{{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 }}

In the 1970s, the 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.{{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}} Hypokalemia causes symptoms of fatigue, muscle weakness, and at its most extreme, paralysis. In addition, about 7% of subjects reported effects on their digestive systems, 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. 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 primates. The potassium deficiency may also be a result of the Chinese diet or genetic predisposition.

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.

Researchers have suggested gossypol might make a good noninvasive alternative to surgical vasectomy.{{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}}

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.{{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 }} 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, 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.

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. Genetically engineered cotton plants that contain little gossypol in the seed may still contain the compound in the stems and leaves.{{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}}

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• {{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