Gossypol
Encyclopedia
Gossypol is a natural phenol
derived from the cotton plant (genus Gossypium
). Gossypol is a phenolic aldehyde
that permeates cells and acts as an inhibitor
for several dehydrogenase
enzyme
s. It is a yellow pigment
.
Among other things, it has been tested as a male oral contraceptive in China
. In addition to its contraceptive properties, gossypol has also long been known to possess antimalarial properties. Other researchers are investigating the anticancer properties of gossypol.
properties, probably due to the regulation of the Bax
and Bcl2. It also reversibly inhibits calcineurin
and binds to calmodulin
. It inhibits replication of the HIV-1 virus
. It is an effective protein kinase
D inhibitor.
It also causes low potassium levels, and thus causes temporary paralysis.
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.
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 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 of hypokalemia
among subjects. Hypokalemia — low blood potassium
levels — causes symptoms of fatigue, muscle weakness, and at its most extreme, paralysis
. In addition, about 7% of subjects reported effects on their digestive system, and about 12% increased fatigue. Most subjects recovered after stopping treatment and taking potassium supplements. A later study showed that taking potassium supplements during gossypol treatment did not prevent hypokalemia in primate
s.
In the mid-1990s, the Brazil
ian 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. Between five and twenty-five percent of the men remained azoospermic up to a year after stopping treatment. The longer the men had taken the drug and the higher their overall dosage, the more likely the men were to have lowered fertility or to become completely infertile. Researchers have suggested that gossypol might make a good non-invasive alternative to surgical vasectomy.
In 1986, the Chinese stopped research because of these side effects.
In 1998, the World Health Organization
's Research Group on Methods for the Regulation of Male Fertility recommended that research should be abandoned. In addition to the other side effects, the WHO researchers were concerned about gossypol's toxicity: the toxic dose in primates is less than 10 times the contraceptive dose. 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
.
microflora can digest gossypol, but only to a certain level, and cottonseed oil must be refined.
A research team at Texas A&M University
, has genetically engineered cotton plants that contain very little gossypol in the seed, but still contain the compound in the stems and leaves. This provides protection against pests and diseases, while allowing the seed to be used for oil and meal for human consumption. The plants are modified by RNA interference
, shutting down the genes for gossypol production in the seed, while leaving them unaffected in the rest of the plant. The resulting gossypol-free cottonseed is then suitable as a high-quality protein
source suitable for consumption not only by cattle, but also by humans, pigs, chickens, or turkeys, making the plant additionally valuable as a food crop. Protein makes up 23% of the cottonseed.
Natural phenol
Natural phenols, bioavailable phenols, plant phenolics, low molecular weight phenols or phenoloids are a class of natural products. They are small molecules containing one or more phenolic group. These molecules are smaller in size than polyphenols, containing less than 12 phenolic groups...
derived from the cotton plant (genus Gossypium
Gossypium
Gossypium is the cotton genus. It belongs to the tribe Gossypieae, in the mallow family, Malvaceae, native to the tropical and subtropical regions from both the Old and New World. The genus Gossypium comprises around 50 species , making it the largest in species number in the tribe Gosssypioieae....
). Gossypol is a phenolic aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
that permeates cells and acts as an inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
for several dehydrogenase
Dehydrogenase
A dehydrogenase is an enzyme that oxidises a substrate by a reduction reaction that transfers one or more hydrides to an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN.-Examples:...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s. It is a yellow pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...
.
Among other things, it has been tested as a male oral contraceptive in China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
. In addition to its contraceptive properties, gossypol has also long been known to possess antimalarial properties. Other researchers are investigating the anticancer properties of gossypol.
Biological properties
It has proapoptoticApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
properties, probably due to the regulation of the Bax
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
and Bcl2. It also reversibly inhibits calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
and binds to calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
. It inhibits replication of the HIV-1 virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
. It is an effective protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
D inhibitor.
It also causes low potassium levels, and thus causes temporary paralysis.
Biosynthesis
Gossypol is a terpeniod aldehyde, which is formed metabolically through acetate via the isoprenoid pathway. Sesquiterpene dimer undergoes a radical coupling reaction to form gossypol. Geranyl pyrophosphate (GPP) and IPP make sesquiterpene precursor, farnesyl diphosphate (FPP), for gossypol. The biosynthesis of gossypol is summarized in figure below. The biosynthesis begins with the 0 compound derived from GPP and IPP. Cadinyl cation (1) is oxidized to 2 by (+)-d-cadinene synthase. The (+)-d-cadinene (2) is involved in making the basic aromatic sesquiterpene unit, homigossypol, by oxidation, which generates the 3 (8-hydroxy-d-cadinene) with the help of (+)-d-cadinene 8-hyroxylase. At 5, the 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 8 (gossypol). The coupling is catalyzed by a hydrogen peroxide-dependent peroxidise enzyme, which results in the final product.Contraceptive use
A 1929 investigation in JiangxiJiangxi
' is a southern province in the People's Republic of China. Spanning from the banks of the Yangtze River in the north into hillier areas in the south, it shares a border with Anhui to the north, Zhejiang to the northeast, Fujian to the east, Guangdong to the south, Hunan to the west, and Hubei to...
showed correlation between low fertility in males and use of crude cottonseed oil
Cottonseed oil
Cottonseed oil is a cooking oil extracted from the seeds of cotton plant of various species, mainly Gossypium hirsutum and Gossypium herbaceum...
for cooking. The compound causing the contraceptive effect was determined to be gossypol.
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 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 of hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
among subjects. Hypokalemia — low blood potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
levels — causes symptoms of fatigue, muscle weakness, and at its most extreme, paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
. In addition, about 7% of subjects reported effects on their digestive system, and about 12% increased fatigue. Most subjects recovered after stopping treatment and taking potassium supplements. A later study showed that taking potassium supplements during gossypol treatment did not prevent hypokalemia in primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s.
In the mid-1990s, the Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
ian 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. Between five and twenty-five percent of the men remained azoospermic up to a year after stopping treatment. The longer the men had taken the drug and the higher their overall dosage, the more likely the men were to have lowered fertility or to become completely infertile. Researchers have suggested that gossypol might make a good non-invasive alternative to surgical vasectomy.
In 1986, the Chinese stopped research because of these side effects.
In 1998, the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
's Research Group on Methods for the Regulation of Male Fertility recommended that research should be abandoned. In addition to the other side effects, the WHO researchers were concerned about gossypol's toxicity: the toxic dose in primates is less than 10 times the contraceptive dose. This report effectively ended further studies of gossypol as a temporary contraceptive, but research into using it as an alternative to vasectomy
Vasectomy
Vasectomy is a surgical procedure for male sterilization and/or permanent birth control. During the procedure, the vasa deferentia of a man are severed, and then tied/sealed in a manner such to prevent sperm from entering into the seminal stream...
continues in Austria
Austria
Austria , officially the Republic of Austria , is a landlocked country of roughly 8.4 million people in Central Europe. It is bordered by the Czech Republic and Germany to the north, Slovakia and Hungary to the east, Slovenia and Italy to the south, and Switzerland and Liechtenstein to the...
, Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
, Chile
Chile
Chile ,officially the Republic of Chile , is a country in South America occupying a long, narrow coastal strip between the Andes mountains to the east and the Pacific Ocean to the west. It borders Peru to the north, Bolivia to the northeast, Argentina to the east, and the Drake Passage in the far...
, China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
, the Dominican Republic
Dominican Republic
The Dominican Republic is a nation on the island of La Hispaniola, part of the Greater Antilles archipelago in the Caribbean region. The western third of the island is occupied by the nation of Haiti, making Hispaniola one of two Caribbean islands that are shared by two countries...
, and Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...
.
Oncology testing
Gossypol is also under investigation as a possible chemotherapy drug, especially in its R- state. It is currently believed that gossypol in itself will not kill cancerous cells; however, it changes the chemistry within the cancer cell and makes it more susceptible to traditional chemotherapy drugs. Phased trials have been done on resistant prostate and lung cancer. Few results have been published to date, so no conclusions can be drawn.Toxicity and potential food source
Food and animal agricultural industries must manage cotton-derivative product levels to avoid toxicity. For example, only ruminantRuminant
A ruminant is a mammal of the order Artiodactyla that digests plant-based food by initially softening it within the animal's first compartment of the stomach, principally through bacterial actions, then regurgitating the semi-digested mass, now known as cud, and chewing it again...
microflora can digest gossypol, but only to a certain level, and cottonseed oil must be refined.
A research team at Texas A&M University
Texas A&M University
Texas A&M University is a coeducational public research university located in College Station, Texas . It is the flagship institution of the Texas A&M University System. The sixth-largest university in the United States, A&M's enrollment for Fall 2011 was over 50,000 for the first time in school...
, has genetically engineered cotton plants that contain very little gossypol in the seed, but still contain the compound in the stems and leaves. This provides protection against pests and diseases, while allowing the seed to be used for oil and meal for human consumption. The plants are modified by RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
, shutting down the genes for gossypol production in the seed, while leaving them unaffected in the rest of the plant. The resulting gossypol-free cottonseed is then suitable as a high-quality protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
source suitable for consumption not only by cattle, but also by humans, pigs, chickens, or turkeys, making the plant additionally valuable as a food crop. Protein makes up 23% of the cottonseed.