Gossypol () is a natural phenol derived from the cotton plant (genus ''

Gossypium ''Gossypium'' () is a genus of flowering plants in the tribe Gossypieae of the mallow family, Malvaceae, from which cotton is harvested. It is native to tropical and subtropical regions of the Old and New Worlds. There are about 50 ''Gossypiu ...

''). Gossypol is a phenolic

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

that permeates cells and acts as an inhibitor for several

dehydrogenase A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as f ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s. It is a yellow

pigment A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...

. The structure exhibits

atropisomerism Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual co ...

, with the two

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

s having different biochemical properties. Among other applications, it has been tested as a

male oral contraceptive Male contraceptives, also known as male birth control, are methods of preventing pregnancy that solely involve the male physiology. The most common kinds of male contraception include condoms, outercourse, and vasectomy. In domestic animals, ca ...

China China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's most populous country, with a population exceeding 1.4 billion, slightly ahead of India. China spans the equivalent of five time zones and ...

. In addition to its putative contraceptive properties, gossypol has also long been known to possess

antimalarial Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young ...

properties.

Biosynthesis

Gossypol is a

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...

which is formed metabolically through acetate via the

isoprenoid pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...

. The

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modificat ...

dimer undergoes a radical coupling reaction to form gossypol. The biosynthesis begins when

geranyl pyrophosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products. Occurrence GPP is an intermediate in the isoprenoid ...

(GPP) and

isopentenyl pyrophosphate Isopentenyl pyrophosphate (IPP, isopentenyl diphosphate, or IDP) is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway (commonly called the mevalonate pathway) and in the ''non-mevalonate'' MEP pathway of i ...

(IPP) are combined to make the

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 Oxidative coupling in chemistry is a coupling reaction of two molecular entities through an oxidative process. Usually oxidative couplings are catalysed by a transition metal complex like in classical cross-coupling reactions, although the underly ...

, ''ortho'' to the phenol groups, to form gossypol (8). The coupling is catalyzed by a

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%� ...

-dependent

peroxidase Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides. Functionality Peroxidases typically ca ...

enzyme, which results in the final product. : Gossypol biosyn

Research

Contraception

A 1929 investigation in

Jiangxi Jiangxi (; ; formerly romanized as Kiangsi or Chianghsi) is a landlocked province in the east of the People's Republic of China. Its major cities include Nanchang and Jiujiang. Spanning from the banks of the Yangtze river in the north int ...

showed correlation between low

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...

in males and use of crude

cottonseed oil Cottonseed oil is cooking oil from the seeds of cotton plants of various species, mainly ''Gossypium hirsutum'' and ''Gossypium herbaceum'', that are grown for cotton fiber, animal feed, and oil. Cotton seed has a similar structure to other oi ...

for cooking. The compound causing the contraceptive effect was determined to be gossypol. In the 1970s, the

Chinese government The Government of the People's Republic of China () is an authoritarian political system in the People's Republic of China under the exclusive political leadership of the Chinese Communist Party (CCP). It consists of legislative, executive, mili ...

began researching the use of gossypol as a

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

. 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 is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

among subjects. Hypokalemia (low blood

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...

levels) causes symptoms of

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, muscle weakness, and at its most extreme,

paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...

. In addition, about 7% of subjects reported effects on their

digestive system The human digestive system consists of the gastrointestinal tract plus the accessory organs of digestion (the tongue, salivary glands, pancreas, liver, and gallbladder). Digestion involves the breakdown of food into smaller and smaller compone ...

s, and about 12% had increased fatigue. 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 Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...

s. The potassium deficiency may also be a result of the Chinese diet or genetic predisposition. In the mid-1990s, the

Brazil Brazil ( pt, Brasil; ), officially the Federative Republic of Brazil (Portuguese: ), is the largest country in both South America and Latin America. At and with over 217 million people, Brazil is the world's fifth-largest country by area ...

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. 5% to 25% of the men remained

azoospermic Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen ...

up to a year after stopping treatment. Researchers have suggested gossypol might make a good noninvasive alternative to surgical

vasectomy Vasectomy, or vasoligation, is an elective surgical procedure for male sterilization or permanent contraception. During the procedure, the male vasa deferentia are cut and tied or sealed so as to prevent sperm from entering into the urethra and ...

. In 1998, the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

's Research Group on Methods for the Regulation of Male Fertility recommended the research should be abandoned. In addition to the other side effects, the WHO researchers were concerned about gossypol's toxicity: the in primates is less than 10 times the contraceptive dose, creating a small

therapeutic window The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...

. 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 Ruminants (suborder Ruminantia) are ungulate, hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by Enteric fermentation, fermenting it in a specialized stomach prior to digestion, principally ...

microflora Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found to ...

can digest gossypol, and then only to a certain level, and

must be refined.

Genetically engineered Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...

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

References

External links

* {{Commons category inline, Gossypol Contraception for males Plant toxins Suspected embryotoxins Dimers (chemistry) Aromatic aldehydes Naphthols Catechols Isopropyl compounds Cotton 3-Hydroxypropenals