Capsaicin

Chembox new
ImageFile1 = Capsaicin_chemical_structure.png ImageSize1 = 250px
ImageFile2 = Capsaicin-3D-vdW.png ImageSize2 = 250px
IUPACName = 8-Methyl-N-vanillyl-trans-6-nonenamide
OtherNames = (E)-N-(4-Hydroxy-3-methoxybenzyl)
-8-methylnon-6-enamide,
trans-8-Methyl-N-vanillylnon
-6-enamide, (E)-Capsaicin,
CPS, C
Section1 = Chembox Identifiers
CASNo = 404-86-4
EINECS = 206-969-8
PubChem = 1548943
SMILES = CC(C)/C=C/CCCCC(NCC1=CC(OC)=C(O)C=C1)=O
Section2 = Chembox Properties
Formula = (CH₃)₂CHCH=CH(CH₂)₄
CONHCH₂C₆H₃-4-(OH)-3-(OCH₃)
C₁₈H₂₇NO₃
MolarMass = 305.41 g/mol
Appearance =
Density =
MeltingPt = 62 - 65 °C
BoilingPt = 210 - 220 °C
Solubility =
Section3 = Chembox Hazards
MainHazards = Toxic (T)
RPhrases = R24/25
SPhrases = S26, S36/37/39, S45
FlashPt =
Autoignition =

Capsaicin IPA|/kæpse.sn/ (8-methyl-"N"-vanillyl-6-nonenamide) is the active component of chili peppers, which are plants belonging to the genus "Capsicum". It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact. Capsaicin and several related compounds are called capsaicinoids and are produced as a secondary metabolite by chili peppers, probably as deterrents against certain herbivores and fungi [http://www.npr.org/templates/story/story.php?storyId=93636630 What Made Chili Peppers So Spicy?] Talk of the Nation, 15 Aug 2008.] . Pure capsaicin is a hydrophobic, colorless, odorless, crystalline to waxy compound.

History

The molecule was first isolated in 1816 in crystalline form by P. A. Bucholz and again 30 years later by L.T. Thresh, who gave it the name "capsaicin." [J King, H Wickes Felter, J Uri Lloyd (1905) A King's American Dispensatory. Eclectic Medical Publications (ISBN 1888483024)] In 1878, the Hungarian doctor Endre Hogyes (calling it capsicol) isolated it and proved that it not only caused the burning feeling when in contact with mucous membranes but also increased secretion of gastric juice. The structure of capsaicin was partly elucidated by E. K. Nelson in 1919. [E. K. Nelson. The constitution of capsaicin, the pungent principle of capsicum. "J. Am. Chem. Soc." 1919, "41", 1115-1121. doi|10.1021/ja02228a011] Capsaicin was first synthesized in 1930 by E. Spath and F. S. Darling. In 1961, similar substances were isolated from chili peppers by the Japanese chemists S. Kosuge and Y. Inagaki, who named them capsaicinoids. [S Kosuge, Y Inagaki, H Okumura (1961). Studies on the pungent principles of red pepper. Part VIII. On the chemical constitutions of the pungent principles. Nippon Nogei Kagaku Kaishi (J. Agric. Chem. Soc.), 35, 923-927; (en) Chem. Abstr. 1964, 60, 9827g. ] [ (ja) S Kosuge, Y Inagaki (1962) Studies on the pungent principles of red pepper. Part XI. Determination and contents of the two pungent principles. Nippon Nogei Kagaku Kaishi (J. Agric. Chem. Soc.), 36, pp.251]

Capsaicinoids

Capsaicin is the main capsaicinoid in chili peppers, followed by dihydrocapsaicin. These two compounds are also about twice as potent to the taste and nerves as the minor capsaicinoids nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. Dilute solutions of pure capsaicinoids produced different types of pungency; however, these differences were not noted using more concentrated solutions.

Capsaicin is believed to be synthesized in the interlocular septa of chili peppers by addition of a branched-chain fatty acid to vanillylamine. Biosynthesis depends on the gene "AT3", which resides at the "pun1" locus, and which encodes a putative acyltransferase. [cite journal |author=Stewart C, Kang BC, Liu K, "et al" |title=The Pun1 gene for pungency in pepper encodes a putative acyltransferase |journal=Plant J. |volume=42 |issue=5 |pages=675–88 |year=2005 |month=June |pmid=15918882 |doi=10.1111/j.1365-313X.2005.02410.x |url=]

Besides the six natural capsaicinoids, one synthetic member of the capsaicinoid family exists. Vanillylamide of n-nonanoic acid (VNA) is used as a reference substance for determining the relative pungency of capsaicinoids.

Natural function

Capsaicin is present in large quantities in the placental tissue (which holds the seeds), the internal membranes and, to a lesser extent, the other fleshy parts of the fruits of plants in the genus "Capsicum". Contrary to popular belief, the seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the white pith around the seeds. [cite web| author=New Mexico State University - College of Agriculture and Home Economics| title=Chile Information -Frequently Asked Questions| year=2005| url=http://spectre.nmsu.edu/dept/academic.html?i=1274&s=sub| accessdate=May 17| accessyear=2007]

The seeds of "Capsicum" plants are predominantly dispersed by birds, as birds lack the receptor to detect capsaicin (i.e., because they cannot sense capsaicin, it is not an irritant to birds). Chili pepper seeds consumed by birds pass through the digestive tract unharmed, whereas those consumed by mammals do not germinate at all. The presence of capsaicin in the fruits therefore protects them from being consumed by mammals, which have molars that can kill seeds.

There is evidence that capsaicin first emerged as an anti-fungal agent.

In 2006 it was discovered that tarantula venom activates the same pathway of pain as is activated by capsaicin, the first demonstrated case of such a shared pathway in both plant and animal anti-mammal defense. [cite journal |author=Siemens J, Zhou S, Piskorowski R, "et al" |title=Spider toxins activate the capsaicin receptor to produce inflammatory pain |journal=Nature |volume=444 |issue=7116 |pages=208–12 |year=2006 |month=November |pmid=17093448 |doi=10.1038/nature05285 |url=]

Uses

Food

Because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes, it is commonly used in food products to give them added spice or "heat" (pungency). In high concentrations capsaicin will also cause a burning effect on other sensitive areas of skin. The degree of heat found within a food is often measured on the Scoville scale.

Cooling and mechanical stimulation are the only proven methods to relieve the pain; capsaicin is not water-soluble, so water and most other liquids will only dull the pain by cooling the area, but will not have any lasting effect. The burning sensation will slowly fade away if no actions are taken. Dairy products are one of the most effective forms of relief; casein, a phosphoprotein found in milk, acts as a detergent to dissociate the capsaicin from nerve receptors, allowing it to wash away. (Dustrophsky, 2006). [cite web| author=Dave DeWitt | title=Burning in the Mouth, Fire in the Belly| year=1999| url=http://www.fiery-foods.com/dave/taste9.html| accessdate=May 18| accessyear=2007]

It is common for people to experience pleasurable and even euphoriant effects from eating capsaicin-flavored foods. Folklore among self-described "pepperheads" attributes this to pain-stimulated release of endorphins, a different mechanism from the local receptor overload that makes capsaicin effective as a topical analgesic. In support of this theory, there is some evidence that the effect can be blocked by naloxone and other compounds that compete for receptor sites with endorphins and opiates.Fact|date=April 2008

Medical

Further|Health risks of chilli consumption and Health benefits of chilli consumptionCapsaicin is currently used in topical ointments to relieve the pain of peripheral neuropathy such as post-herpetic neuralgia caused by shingles. It may be used in concentrations of between 0.025% and 0.075%. It may be used as a cream for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains. The treatment typically involves the application of a topical anesthetic until the area is numb. Then the capsaicin is applied by a therapist wearing rubber gloves and a face mask. The capsaicin remains on the skin until the patient starts to feel the "heat", at which point it is promptly removed. Capsaicin is also available in large bandages that can be applied to the back.

Recently, capsaicin is being tested for the prevention of pain post surgery. David Julius, a physiology professor at the University of California, San Francisco, recently discovered that capsaicin selectively binds to a protein known as TRPV1 that resides on the membranes of pain and heat sensing neurons. TRPV1 a heat activated calcium channel, with a threshold to open between 37 and 45 Celsius degrees (37 degrees is normal body temperature). When capsaicin binds to TRPV1, it causes the channel to lower its opening threshold, thereby opening it at temperatures less than the body's temperature, which is why capsaicin is linked to the sensation of heat. Prolonged activation of these neurons by capsaicin depletes presynaptic substance P, one of the body's neurotransmitters for pain and heat. Neurons that do not contain TRPV1 are unaffected. [ [http://www.sciam.com/article.cfm?articleID=674E972E-E7F2-99DF-39A3406D0D2B2A7C&chanID=sa007 Chili Pepper Cocktail Blunts Pain: Scientific American ] ] This causes extended numbness following surgery, and the patient does not feel pain as the capsaicin is applied under anesthesia.

The result appears to be that the chemical mimics a burning sensation, the nerves are overwhelmed by the influx, and are unable to report pain for an extended period of time. With chronic exposure to capsaicin, neurons are depleted of neurotransmitters and it leads to reduction in sensation of pain and blockade of neurogenic inflammation. If capsaicin is removed, the neurons recover.Fact|date=July 2007

Capsaicin is being explored as a possible cure for diabetes by researchers in Toronto, Canada; capsaicin was injected into pancreatic sensory nerves of mice with Type 1 diabetes because of a suspected link between the nerves and diabetes. [cite journal |author=Razavi R, Chan Y, Afifiyan FN, "et al" |title=TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes |journal=Cell |volume=127 |issue=6 |pages=1123–35 |year=2006 |month=December |pmid=17174891 |doi=10.1016/j.cell.2006.10.038 |url=]

The American Association for Cancer Research reports studies suggesting capsaicin is able to kill prostate cancer cells by causing them to undergo apoptosis.cite journal | last=Mori | first=A | coauthors=Lehmann S, O'Kelly J et al. | title=Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells | journal=Cancer Research | volume=66 | issue=6 | pages=3222–3229 | publisher=American Association for Cancer Research | date=March 2006 | url=http://cancerres.aacrjournals.org/cgi/content/full/66/6/3222 | pmid=16540674 |doi=10.1158/0008-5472.CAN-05-0087 | accessdate=2008-07-22 ] [cite web | author=American Association for Cancer Research | title=Pepper component hot enough to trigger suicide in prostate cancer cells | year=2006 | url=http://www.eurekalert.org/pub_releases/2006-03/aafc-pch031306.php | accessdate=January 27 | accessyear=2007 ] The studies were performed on tumors formed by human prostate cancer cell cultures grown in mouse models, and showed tumors treated with capsaicin were about one-fifth the size of the untreated tumors. It has long been noted that in Thailand, where much spicy food is consumed, there is very low incidence of gastrointestinal cancers, including colorectal and stomach cancers, compared to the rest of Asia, including Japan and China.cite journal | last=Vatanasapt | first=V | coauthors=Martin N, Sriplung H et al. | title=Cancer incidence in Thailand, 1988-1991 | journal=Cancer Epidemiology, Biomarkers & Prevention | volume=4 | issue=5 | pages=475–483 | publisher=American Association for Cancer Research | date=Jul-Aug 1995 | url=http://cebp.aacrjournals.org/cgi/reprint/4/5/475 | pmid=7549802 | accessdate=2008-07-22 ] Mexico also has low rates of the same cancers compared to the USA.Fact|date=November 2007 Several recent studies have shown that capsaicin may actually prevent the growth of certain types of cancer.Fact|date=November 2007 In particular, there have been several clinical studies conducted in Japan and China that showed natural capsaicin directly inhibits the growth of leukemic cells.cite journal | last=Ito | first=K | coauthors=Nakazato T, Yamato K et al. | title=Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species | journal=Cancer Research | volume=64 | issue=3 | pages=1071–1078 | publisher=American Association for Cancer Research | date=February 2004 | url=http://cancerres.aacrjournals.org/cgi/content/full/64/3/1071 | pmid=14871840 | accessdate=2008-07-22 ] Although these studies used pure capsaicin directly injected into isolated diseased cells in a laboratory setting, scientists have also concluded that daily consumption of hot peppers (thus capsaicin) may actually prevent certain types of cancer. Throughout South America, intestinal, stomach, and colon cancer rates are very low compared to the United States.Fact|date=November 2007

Another study carried out at the University of Nottingham suggests capsaicin is able to trigger apoptosis in human lung cancer cells as well. [cite web| author=BBC News| title=How spicy foods can kill cancers| year=2007 | url=http://news.bbc.co.uk/2/hi/health/6244715.stm| accessdate=January 09| accessyear=2007]

Capsaicin is also the key ingredient in the experimental drug [http://www.anesiva.com/wt/page/adlea Adlea] , which is in Phase 2 trials as a long-acting analgesic to treat post-surgical and osteoarthritis pain for weeks to months after a single injection to the site of pain. [cite web |url=http://www.mail.com/Article.aspx?articlepath=APNews%5CTop%20Headlines%5C20071030%5CHealthBeat_Peppers___Pain_20071030.xml&cat=topheadlines&subcat=&pageid=1 |title=Doctors Test Hot Sauce For Pain Relief |accessdate=2007-10-30]

Proposed drug abuse deterrent

Clifford Woolf, the Richard J. Kitz Professor of Anesthesia Research at Harvard Medical School, has suggested using capsaicin to deter abuse of certain extended-release drugs such as OxyContin and Ritalin. [Cromie WJ (2006) "Using chilli peppers to burn drug abusers" [http://www.news.harvard.edu/gazette/daily/2004/12/21-capsaicin.html "Harvard University Gazette" accessed 24 January 2006] ] When taken as prescribed, opioid prescription drugs such as OxyContin or stimulant drugs such as Adderall XR release their active chemical over time, but when crushed and snorted, taken as a suppository, chewed, or injected, the larger than normal dosage is absorbed all at once and a much stronger effect is produced that can be highly habit forming and dangerous due to the higher risk of overdose. Woolf has argued that adding capsaicin into the capsules would be a safe way to deter abuse. A person taking the capsule in the prescribed way ("i.e.," swallowing it whole) would suffer no ill effects from the additive. However, a person crushing it would expose the irritant. Anyone then swallowing it, snorting it, or injecting it would be exposed to the full power of the chemical. "Imagine snorting an extract of 50 jalapeño peppers and you get the idea," Woolf said in an interview with the Harvard University Gazette. As of 2006, Woolf's proposal is still in the preliminary stages of development and the additive has not yet entered the production stage.

Non-lethal force

Capsaicin is also the active ingredient in riot control and personal defense pepper spray chemical agents. When the spray comes in contact with skin, especially eyes or mucous membranes, it is very painful, and breathing small particles of it as it disperses can cause breathing difficulty, which serves to discourage assailants. Refer to the Scoville scale for a comparison of pepper spray to other sources of capsaicin.

In large quantities, capsaicin can cause death. Symptoms of overdose include difficulty breathing, blue skin, and convulsions. The large amount needed to kill an adult human and the low concentration of capsaicin in chilies make the risk of accidental poisoning by chili consumption negligible.

Pest deterrent

Capsaicin is also used to deter pests. A common example is the use of ground-up or crushed dried chili pods in birdseed to deter squirrels, since birds are unaffected by capsaicin. Insects that feed on pepper, most aquatic organisms (most notably sharks), and related plants are also unaffected.

Another example is the use of chili peppers by the Elephant Pepper Development Trust to improve crop security for rural communities in Africa.

Equestrian sports

Capsaicin is a banned substance in equestrian sports because of its hypersensitizing and pain relieving properties. At the show jumping events of the 2008 Summer Olympics, four horses tested positive for the substance, resulting in disqualification. [http://news.bbc.co.uk/sport1/hi/olympics/equestrian/7574220.stm]

Mechanism of action

The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons. Capsaicin, as a member of the vanilloid family, binds to a receptor called the vanilloid receptor subtype 1 (VR1). [cite journal
author=Story GM, Crus-Orengo L
title=Feel the burn
journal=American Scientist
volume=95
issue= 4
pages= 326–333
year= 2007
issn=0003-0996
month= July-August
doi=10.1511/2007.66.326 ] First cloned in 1997, VR1 is an ion channel-type receptor. VR1, which can also be stimulated with heat and physical abrasion, permits cations to pass through the cell membrane and into the cell when activated. The resulting depolarization of the neuron stimulates it to signal the brain. By binding to the VR1 receptor, the capsaicin molecule produces the same sensation that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin is described as a burning sensation.

The VR1 ion channel has subsequently been shown to be a member of the superfamily of TRP ion channels, and as such is now referred to as Gene|TRPV1. There are a number of different TRP ion channels that have been shown to be sensitive to different ranges of temperature and probably are responsible for our range of temperature sensation. Thus, capsaicin does not actually cause a chemical burn, or indeed any damage to tissue at all; it causes only the sensation of one.

Toxicity

Acute health effects

Capsaicin is a highly irritant material requiring proper protective goggles, respirators, and proper hazmat handling procedures. It is hazardous in cases of skin contact (irritant, sensitizer), of eye contact (irritant), of ingestion, of inhalation (lung irritant, lung sensitizer). Severe over-exposure to pure capsaicin can result in death; the lethal dose (LD50 in mice) is 47.2 mg/kg.Cite web|url=http://www.sciencelab.com/xMSDS-Capsaicin_Natural-9923296|title=Capsaicin Material Safety Data Sheet|accessdate=2007-07-13|publisher=sciencelab.com|year=2007|format=pdf] .

Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers.cite book | title=Goldfrank's Toxicologic Emergencies| last=Goldfrank| first=L R. (ed.)| pages=1167| publisher=McGraw-Hill| location=New York, New York] They cause burning or stinging pain to the skin, and if ingested in large amounts by adults or small amounts by children, can produce nausea, vomiting, abdominal pain, and burning diarrhea. Eye exposure produces intense tearing, pain, conjunctivitis, and blepharospasm.

Treatment after exposure

The primary treatment is removal from exposure. Contaminated clothing should be removed and placed in airtight bags to prevent secondary exposure. Capsaicin could be washed off the skin using soap, shampoo, or other detergents, or rubbed off with oily compounds such as vegetable oil, paraffin oil, petroleum jelly (Vaseline), creams, or polyethylene glycol. Plain water, as well as home remedies such as vinegar, bleach, sodium metabisulfite, or topical antacid suspensions are ineffective in removing capsaicin.

Burning and pain symptoms can be effectively relieved by cooling, "e.g.", from ice, cold water, cold bottles, cold surfaces, or a flow of air from wind or a fan. In severe cases, eye burn might be treated symptomatically with topical ophthalmic anesthetics; mucous membrane burn with lidocaine gel. Capsaicin-induced asthma might be treated with nebulized bronchodilators or oral antihistamines or corticosteroids.

Effects of dietary consumption

Ingestion of spicy food or ground jalapeño peppers does not cause mucosal erosions or other abnormalities.cite journal | author=Graham DY, Smith JL, Opekun AR.| title=Spicy food and the stomach. Evaluation by videoendoscopy.| journal=JAMA| year=1988| volume=260| issue=23| page=3473-5| url= | pages = 3473 | doi = 10.1001/jama.260.23.3473| pmid=3210286] Some mucosal microbleeding has been found after eating red and black peppers, but there is no significant difference between aspirin (used as a control) and peppers.cite journal |author=Myers BM, Smith JL, Graham DY |title=Effect of red pepper and black pepper on the stomach |journal=Am. J. Gastroenterol. |volume=82 |issue=3 |pages=211–4 |year=1987 |month=March |pmid=3103424 |doi= |url=] Other studies have shown an association between chronic consumption of capsaicin-rich foods and stomach cancer.cite journal |author=López-Carrillo L, López-Cervantes M, Robles-Díaz G, "et al" |title=Capsaicin consumption, Helicobacter pylori positivity and gastric cancer in Mexico |journal=Int. J. Cancer |volume=106 |issue=2 |pages=277–82 |year=2003 |pmid=12800206 |doi=10.1002/ijc.11195]

References

Footnotes

General references

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* Garnanez RJ, McKee LH (2001) "Temporal effectiveness of sugar solutions on mouth burn by capsaicin" [http://ift.confex.com/ift/2001/techprogram/paper_8185.htm IFT Annual Meeting 2001]
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* Tarantula Venom, Chili Peppers Have Same "Bite," Study Finds http://news.nationalgeographic.com/news/2006/11/061108-tarantula-venom.html

See also

* TRPV1, the only known receptor (a transient receptor potential channel) for capsaicin.
* Piperine, the active piquant chemical in black pepper
* Allyl isothiocyanate, the active piquant chemical in mustard, radishes, horseradish, and wasabi
* Allicin, the active piquant flavor chemical in uncooked garlic and onions (see those articles for discussion of other chemicals in them relating to pungency, and eye irritation)
* Naga Jolokia pepper, the world's most capsaicin-rich fruit

External links

* [http://www.epa.gov/oppsrrd1/REDs/factsheets/4018fact.pdf EPA Capsaicin Reregistration Eligibility Decision Fact Sheet]
* [http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_784.html Capsaicin and Its Therapeutic Potential]
* [http://www.chm.bris.ac.uk/motm/chilli/capsaicin.htm Molecule of the Month]
* [http://www.habaneros.org/chili/index.html The Magic of Chili Pepper and Capsaicin]
* [http://ec.europa.eu/food/fs/sc/scf/out120_en.pdf European Commission] , opinion of the Scientific Committee on Food on capsaicin.
* A WikiHow article on [http://www.wikihow.com/Cool--Burns-from-Chilli-Peppers How to Cool Chilli Pepper Burns] .
* The Neurobiology of Disease wiki, from Connecticut College: [http://nutmeg.conncoll.edu/Neurobiology-of-Disease/index.php/Capsaicin Capsaicin] .