Capsaicin

Capsaicin
Names
Preferred IUPAC name
(6E)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
Other names
(E)-N-(4-Hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide
8-Methyl-N-vanillyl-trans-6-nonenamide
trans-8-Methyl-N-vanillylnon-6-enamide
(E)-Capsaicin
Capsicine
Capsicin
CPS
Identifiers
404-86-4 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:3374 YesY
ChEMBL ChEMBL294199 YesY
ChemSpider 1265957 YesY
ECHA InfoCard 100.006.337
EC Number 206-969-8
2486
KEGG C06866 YesY
PubChem 1548943
UNII S07O44R1ZM YesY
Properties
C18H27NO3
Molar mass 305.42 g·mol−1
Appearance crystalline white powder[1]
Odor highly volatile and pungent
Melting point 62 to 65 °C (144 to 149 °F; 335 to 338 K)
Boiling point 210 to 220 °C (410 to 428 °F; 483 to 493 K) 0.01 Torr
0.0013 g/100 mL
Solubility soluble in alcohol, ether, benzene
slightly soluble in CS2, HCl, petroleum
UV-vis (λmax) 280 nm
Structure
monoclinic
Pharmacology
M02AB01 (WHO) N01BX04 (WHO)
Hazards
Main hazards Toxic (T)
Safety data sheet Capsaicin, Natural MSDS
R-phrases R24/25
S-phrases S26, S36/37/39, S45
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
2
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references
Capsaicin
Heat Above Peak (SR: 15,000,000-16,000,000)

Capsaicin (/kæpˈseɪ.ᵻsɪn/ (INN); 8-methyl-N-vanillyl-6-nonenamide) is an 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 secondary metabolites by chili peppers, probably as deterrents against certain mammals and fungi.[2] Pure capsaicin is a volatile, hydrophobic, colorless, odorless, crystalline to waxy compound.

History

The compound was first extracted in impure form in 1816 by Christian Friedrich Bucholz (1770–1818).[3] He called it "capsicin", after the genus Capsicum from which it was extracted. John Clough Thresh (1850–1932), who had isolated capsaicin in almost pure form,[4][5] gave it the name "capsaicin" in 1876.[6] Karl Micko isolated capsaicin in its pure form in 1898.[7][8] Capsaicin's chemical composition was first determined by E. K. Nelson in 1919, who also partially elucidated capsaicin's chemical structure.[9] Capsaicin was first synthesized in 1930 by Ernst Spath and Stephen F. Darling.[10] In 1961, similar substances were isolated from chili peppers by the Japanese chemists S. Kosuge and Y. Inagaki, who named them capsaicinoids.[11][12]

In 1873 German pharmacologist Rudolf Buchheim[13] (1820–1879) and in 1878 the Hungarian doctor Endre Hőgyes[14] stated that "capsicol" (partially purified capsaicin[15]) caused the burning feeling when in contact with mucous membranes and increased secretion of gastric acid.

Capsaicinoids

The most commonly occurring capsaicinoids are capsaicin (69%), dihydrocapsaicin (22%) and nordihydrocapsaicin (7%), homocapsaicin (1%), and homodihydrocapsaicin (1%) [16]

Besides the five natural capsaicinoids (table below), one synthetic member of the capsaicinoid family exists: vanillylamide of n-nonanoic acid (VNA, also PAVA) used as a reference substance for determining the relative pungency of capsaicinoids.

Capsaicinoid name Abbrev. Typical
relative
amount 		Scoville
heat units 		Chemical structure
Capsaicin C 69% 16,000,000
Dihydrocapsaicin DHC 22% 15,000,000
Nordihydrocapsaicin NDHC 7% 9,100,000
Homodihydrocapsaicin HDHC 1% 8,600,000
Homocapsaicin HC 1% 8,600,000
Nonivamide PAVA 9,200,000

Biosynthesis

History

The general biosynthetic pathway of capsaicin and other capsaicinoids was elucidated in the 1960s by Bennett and Kirby, and Leete and Louden. Radiolabeling studies identified phenylalanine and valine as the precursors to capsaicin.[17][18] Enzymes of the phenylpropanoid pathway, phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), caffeic acid O-methyltransferase (COMT) and their function in capsaicinoid biosynthesis were identified later by Fujiwake et al.,[19][20] and Sukrasno and Yeoman.[21] Suzuki et al. are responsible for identifying leucine as another precursor to the branched-chain fatty acid pathway.[22] It was discovered in 1999 that pungency of chili peppers is related to higher transcription levels of key enzymes of the phenylpropanoid pathway, phenylalanine ammonia lyase, cinnamate 4-hydroxylase, caffeic acid O-methyltransferase. Similar studies showed high transcription levels in the placenta of chili peppers with high pungency of genes responsible for branched-chain fatty acid pathway.[23]

Biosynthetic Pathway

Plants exclusively of the Capsicum genus produce capsaicinoids, which are alkaloids.[24] Capsaicin is believed to be synthesized in the interlocular septum of chili peppers and depends on the gene AT3, which resides at the pun1 locus, and which encodes a putative acyltransferase.[25]

Biosynthesis of the capsaicinoids occurs in the glands of the pepper fruit where capsaicin synthase condenses vanillylamine from the phenylpropanoid pathway with an acyl-CoA moiety produced by the branched-chain fatty acid pathway.[26][27][28][29]

Capsaicin is the most abundant capsaicinoid found in the Capsicum genus, but at least ten other capsaicinoid variants exist.[30] Phenylalanine supplies the precursor to the phenylpropanoid pathway while leucine or valine provide the precursor for the branched-chain fatty acid pathway.[26][27] To produce capsaicin, 8-methyl-6-nonenoyl-CoA is produced by the branched-chain fatty acid pathway and condensed with vanillamine. Other capsaicinoids are produced by the condensation of vanillamine with various acyl-CoA products from the branched-chain fatty acid pathway, which is capable of producing a variety of acyl-CoA moieties of different chain length and degrees of unsaturation.[31] All condensation reactions between the products of the phenylpropanoid and branched-chain fatty acid pathway are mediated by capsaicin synthase to produce the final capsacinoid product.[26][27]

Vanillamine is a product of the phenylpropanoid pathway
Valine enters the branced fatty acid pathway to produce 8-methyl-6-nonenoyl-CoA
Capsaicin synthase condenses vanillamine and 8-methy-6-nonenoyl CoA to produce capsaicin

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. The seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the white pith of the inner wall, where the seeds are attached.[32]

The seeds of Capsicum plants are dispersed predominantly by birds: in birds, the TRPV1 channel does not respond to capsaicin or related chemicals (avian vs. mammalian TRPV1 show functional diversity and selective sensitivity). This is advantageous to the plant, as chili pepper seeds consumed by birds pass through the digestive tract and can germinate later, whereas mammals have molar teeth which destroy such seeds and prevent them from germinating. Thus, natural selection may have led to increasing capsaicin production because it makes the plant less likely to be eaten by animals that do not help it disperse.[33] There is also evidence that capsaicin may have evolved as an anti-fungal agent:[34] the fungal pathogen Fusarium, which is known to infect wild chilies and thereby reduce seed viability, is deterred by capsaicin, which thus limits this form of predispersal seed mortality.

In 2006, it was discovered that the venom of a certain tarantula species activates the same pathway of pain as is activated by capsaicin; this was the first demonstrated case of such a shared pathway in both plant and animal anti-mammal defense.[35]

Uses

Food

Curry dishes

Because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes, it is commonly used in food products to provide added spice or "heat" (piquancy), usually in the form of spices such as chili powder and paprika.[36] In high concentrations, capsaicin will also cause a burning effect on other sensitive areas, such as skin or eyes.[37] The degree of heat found within a food is often measured on the subjective Scoville scale.[36] In some cases, because people enjoy the heat,[36] there has long been a demand for capsaicin-spiced products like curry, chili con carne, and hot sauces such as Tabasco sauce and salsa.[36]

It is common for people to experience pleasurable and even euphoric effects from ingesting capsaicin.[36] Folklore among self-described "chiliheads" attributes this to pain-stimulated release of endorphins, a different mechanism from the local receptor overload that makes capsaicin effective as a topical analgesic.[37]

Research and pharmaceutical use

Capsaicin is used as an analgesic in topical ointments, nasal sprays (Sinol-M), and dermal patches to relieve pain, typically in concentrations between 0.025% and 0.1%.[38] It may be applied in cream form for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, backache, strains and sprains, often in compounds with other rubefacients.[38]

It is also used to reduce the symptoms of peripheral neuropathy such as post-herpetic neuralgia caused by shingles.[38] Capsaicin transdermal patch (Qutenza) for the management of this particular therapeutic indication (pain due to post-herpetic neuralgia) was approved as a therapeutic by the U.S. FDA,[39] but a subsequent application for Qutenza to be used as an analgesic in HIV neuralgia was refused.[40]

Although capsaicin creams have been used to treat psoriasis for reduction of itching,[38][41][42] a review of six clinical trials involving topical capsaicin for treatment of pruritus concluded there was insufficient evidence of effect.[43]

There is insufficient clinical evidence to determine the role of ingested capsaicin on a variety of human disorders, including obesity, diabetes, cancer and cardiovascular diseases.[38]

Pepper spray and pests

Capsaicin is also an active ingredient in riot control and personal defense pepper spray agents.[44][45][46] When the spray comes in contact with skin, especially eyes or mucous membranes, it produces pain and breathing difficulty, discouraging assailants. Refer to the Scoville scale for a comparison of pepper spray to other sources of capsaicin.

Capsaicin is also used to deter pests, specifically mammalian pests. Targets of capsaicin repellants include voles, deer, rabbits, squirrels, bears, insects, and attacking dogs.[47] Ground or crushed dried chili pods may be used in birdseed to deter rodents,[48] taking advantage of the insensitivity of birds to capsaicin. The Elephant Pepper Development Trust claims the use of chili peppers to improve crop security for rural African communities. Notably, an article published in the Journal of Environmental Science and Health in 2006 states that "Although hot chili pepper extract is commonly used as a component of household and garden insect-repellent formulas, it is not clear that the capsaicinoid elements of the extract are responsible for its repellency."[49]

The first pesticide product using solely capsaicin as the active ingredient was registered with the U.S. Department of Agriculture in 1962.[47]

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, which resulted in disqualification.[50]

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 (TRPV1).[51] First cloned in 1997, TRPV1 is an ion channel-type receptor.[52] TRPV1, which can also be stimulated with heat, protons and physical abrasion, permits cations to pass through the cell membrane when activated. The resulting depolarization of the neuron stimulates it to signal the brain. By binding to the TRPV1 receptor, the capsaicin molecule produces similar sensations to those of excessive heat or abrasive damage, explaining why the spiciness of capsaicin is described as a burning sensation.

Early research showed capsaicin to evoke a strikingly long-onset current in comparison to other chemical agonists, suggesting the involvement of a significant rate-limiting factor.[53] Subsequent to this, the TRPV1 ion channel has been shown to be a member of the superfamily of TRP ion channels, and as such is now referred to as 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 direct tissue damage at all, when chili peppers are the source of exposure. The inflammation resulting from exposure to capsaicin is believed to be the result of the body's reaction to nerve excitement. For example, the mode of action of capsaicin in inducing bronchoconstriction is thought to involve stimulation of C fibers[54] culminating in the release of neuropeptides. In essence, the body inflames tissues as if it has undergone a burn or abrasion and the resulting inflammation can cause tissue damage in cases of extreme exposure, as is the case for many substances that cause the body to trigger an inflammatory response.

Toxicity

Acute health effects

Capsaicin is a highly irritant material requiring proper protective goggles, respirators, and proper hazardous material-handling procedures. Capsaicin takes effect upon skin contact (irritant, sensitizer), eye contact (irritant), ingestion, and inhalation (lung irritant, lung sensitizer). The LD50 in mice is 47.2 mg/kg.[55][56]

Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers. 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.[57]

When used for weight loss in capsules, there has been a report of heart attack; this was thought to be due to excess sympathetic output.[58]

Treatment after exposure

The primary treatment is removal from exposure. Contaminated clothing should be removed and placed in airtight bags to prevent secondary exposure.

For external exposure, bathing the mucous membrane surfaces that have contacted capsaicin with oily compounds such as vegetable oil, paraffin oil, petroleum jelly (Vaseline), creams, or polyethylene glycol is the most effective way to attenuate the associated discomfort; since oil and capsaicin are both hydrophobic hydrocarbons the capsaicin that has not already been absorbed into tissues will be picked up into solution and easily removed. Capsaicin can also be washed off the skin using soap, shampoo, or other detergents. Plain water is ineffective at removing capsaicin,[55] as are bleach, sodium metabisulfite and topical antacid suspensions. Capsaicin is soluble in alcohol, which can be used to clean contaminated items.[55]

When capsaicin is ingested, cold milk is an effective way to relieve the burning sensation (due to caseins having a detergent effect on capsaicin[59]); and room-temperature sugar solution (10%) at 20 °C (68 °F) is almost as effective.[60] The burning sensation will slowly fade away over several hours if no actions are taken.

Capsaicin-induced asthma might be treated with oral antihistamines or corticosteroids.[57]

Effects of dietary consumption

Ingestion of spicy food or ground jalapeño peppers does not cause mucosal erosions or other abnormalities.[61]

Effects on weight loss and regain

There is no evidence showing that weight loss is directly correlated with ingesting capsaicin. Well-designed clinical studies have not been performed because the pungency of capsaicin in prescribed doses under research prevents subject compliance.[62]

See also

References

Footnotes

  1. ↑ ChemSpider - Capsaicin
  2. ↑ What Made Chili Peppers So Spicy? Talk of the Nation, 15 August 2008.
  3. ↑ History of early research on capsaicin:
    • Harvey W. Felter and John U. Lloyd, King's American Dispensatory (Cincinnati, Ohio: Ohio Valley Co., 1898), vol. 1, page 435. Available on-line at: Henriette's Herbal.
    • Andrew G. Du Mez, "A century of the United States pharmocopoeia 1820-1920. I. The galenical oleoresins" (Ph.D. dissertation, University of Wisconsin, 1917), pages 111-132. Available on-line at: Archive.org.
    • C. F. Bucholz (1816) "Chemische Untersuchung der trockenen reifen spanischen Pfeffers" [Chemical investigation of dry, ripe Spanish peppers], Almanach oder Taschenbuch für Scheidekünstler und Apotheker (Weimar) [Almanac or Pocket-book for Analysts (Chemists) and Apothecaries], vol. 37, pages 1-30. [Note: Christian Friedrich Bucholz's surname has been variously spelled as "Bucholz", "Bucholtz", or "Buchholz".]
    • The results of Bucholz's and Braconnot's analyses of Capsicum annuum appear in: Jonathan Pereira, The Elements of Materia Medica and Therapeutics, 3rd U.S. ed. (Philadelphia, Pennsylvania: Blanchard and Lea, 1854), vol. 2, page 506.
    • Biographical information about Christian Friedrich Bucholz is available in: Hugh J. Rose, Henry J. Rose, and Thomas Wright, ed.s, A New General Biographical Dictionary (London, England: 1857), vol. 5, page 186.
    • Biographical information about C. F. Bucholz is also available (in German) on-line at: Allgemeine Deutsche Biographie.
    • Some other early investigators who also extracted the active component of peppers:
    1. Benjamin Maurach (1816) "Pharmaceutisch-chemische Untersuchung des spanischen Pfeffers" (Pharmaceutical-chemical investigation of Spanish peppers), Berlinisches Jahrbuch für die Pharmacie, vol. 17, pages 63-73. Abstracts of Maurach's paper appear in: (i) Repertorium für die Pharmacie, vol. 6, page 117-119 (1819); (ii) Allgemeine Literatur-Zeitung, vol. 4, no. 18, page 146 (Feb. 1821); (iii) "Spanischer oder indischer Pfeffer", System der Materia medica ... , vol. 6, pages 381-386 (1821) (this reference also contains an abstract of Bucholz's analysis of peppers).
    2. French chemist Henri Braconnot (1817) "Examen chemique du Piment, de son principe âcre, et de celui des plantes de la famille des renonculacées" (Chemical investigation of the chili pepper, of its pungent principle [constituent, component], and of that of plants of the family Ranunculus), Annales de Chemie et de Physique, vol. 6, pages 122- 131.
    3. Danish geologist Johann Georg Forchhammer in: Hans C. Oersted (1820) "Sur la découverte de deux nouveaux alcalis végétaux" (On the discovery of two new plant alkalis), Journal de physique, de chemie, d'histoire naturelle et des arts, vol. 90, pages 173-174.
    4. German apothecary Ernst Witting (1822) "Considerations sur les bases vegetales en general, sous le point de vue pharmaceutique et descriptif de deux substances, la capsicine et la nicotianine" (Thoughts on the plant bases in general from a pharmaceutical viewpoint, and description of two substances, capsicin and nicotine), Beiträge für die pharmaceutische und analytische Chemie, vol. 3, pages 43ff.
  4. ↑ In a series of articles, J. C. Thresh obtained capsaicin in almost pure form:
    • J. C. Thresh (1876) "Isolation of capsaicin," The Pharmaceutical Journal and Transactions, 3rd series, vol. 6, pages 941-947;
    • J. C. Thresh (8 July 1876) "Capsaicin, the active principle in Capsicum fruits," The Pharmaceutical Journal and Transactions, 3rd series, vol. 7, no. 315, pages 21 ff. [Note: This article is summarized in: "Capsaicin, the active principle in Capsicum fruits," The Analyst, vol. 1, no. 8, pages 148-149, (1876).]. In The Pharmaceutical Journal and Transactions, volume 7, see also pages 259ff and 473 ff and in vol. 8, see pages 187ff;
    • Year Book of Pharmacy… (1876), pages 250 and 543;
    • J. C. Thresh (1877) "Note on Capsaicin," Year Book of Pharmacy…, pages 24-25;
    • J. C. Thresh (1877) "Report on the active principle of Cayenne pepper," Year Book of Pharmacy..., pages 485-488.
  5. ↑ Obituary notice of J. C. Thresh: "John Clough Thresh, M.D., D. Sc., and D.P.H". The British Medical Journal. 1 (3726): 1057–1058. 1932. doi:10.1136/bmj.1.3726.1057-c. PMC 2521090Freely accessible. PMID 20776886.
  6. ↑ J King, H Wickes Felter, J Uri Lloyd (1905) A King's American Dispensatory. Eclectic Medical Publications (ISBN 1888483024)
  7. ↑ Micko K (1898). "Zur Kenntniss des Capsaïcins" [On our knowledge of capsaicin]. Zeitschrift für Untersuchung der Nahrungs- und Genussmittel (Journal for the Investigation of Necessities and Luxuries) (in German). 1: 818–829. doi:10.1007/bf02529190.
  8. ↑ Karl Micko (1899). "Über den wirksamen Bestandtheil des Cayennespfeffers" [On the active component of Cayenne pepper]. Zeitschrift für Untersuchung der Nahrungs- und Genussmittel (in German). 2: 411–412. doi:10.1007/bf02529197.
  9. ↑ Nelson EK (1919). "The constitution of capsaicin, the pungent principle of capsicum". J. Am. Chem. Soc. 41: 1115–1121. doi:10.1021/ja02228a011.
  10. ↑ Späth E, Darling SF (1930). "Synthese des Capsaicins". Chem. Ber. 63B: 737–743.
  11. ↑ 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.
  12. ↑ (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
  13. ↑ Rudolf Buchheim (1873) "Über die 'scharfen' Stoffe" (On the "hot" substance), Archiv der Heilkunde (Archive of Medicine), vol. 14, pages 1ff. See also: R. Buchheim (1872) "Fructus Capsici," Vierteljahresschrift fur praktische Pharmazie (Quarterly Journal for Practical Pharmacy), vol. 4, pages 507ff.; reprinted (in English) in: Proceedings of the American Pharmaceutical Association, vol. 22, pages 106ff (1873).
  14. ↑ Endre Hőgyes, "Adatok a paprika (Capsicum annuum) élettani hatásához" [Data on the physiological effects of the pepper (Capsicum annuum)], Orvos-természettudumányi társulatot Értesítője [Bulletin of the Medical Science Association] (1877); reprinted in: Orvosi Hetilap [Medical Journal] (1878), 10 pages. Published in German as: "Beitrage zur physiologischen Wirkung der Bestandtheile des Capiscum annuum (Spanischer Pfeffer)" [Contributions on the physiological effects of components of Capsicum annuum (Spanish pepper)], Archiv für Experimentelle Pathologie und Pharmakologie, vol. 9, pages 117-130 (1878). See springerlink.com
  15. ↑ F.A. Flückiger, Pharmakognosie des Pflanzenreiches ( Berlin, Germany: Gaertner's Verlagsbuchhandlung, 1891).
  16. ↑ Bennett DJ, Kirby GW (1968). "Constitution and biosynthesis of capsaicin". J. Chem. Soc., C. 442: 442. doi:10.1039/j39680000442.
  17. ↑ [Bennett DJ, Kirby GW (1968) Constitution and biosynthesis of capsaicin. J Chem Soc C 4:442–446]
  18. ↑ [Leete E, Louden MCL (1968) Biosynthesis of capsaicin and dihydrocapsaicin in Capsicum frutescens" J Am Chem Soc 90:6837–6841]
  19. ↑ [Fujiwake H, Suzuki T, Iwai K (1982a) Intracellular distribution of enzymes and intermediates involved in biosynthesis of capsaicin and its analogues in Capsicum fruits. Agric Biol Chem 46:2685–2689]
  20. ↑ [Fujiwake H, Suzuki T, Iwai K (1982b) Capsaicinoid formation in the protoplast from placenta of Capsicum fruits. Agric Biol Chem 46:2591–2592]
  21. ↑ [Sukrasno N, Yeoman MM (1993) Phenylpropanoid metabolism during growth and development of Capsicum frutescens fruits" Phytochemistry 32:839–844]
  22. ↑ [Suzuki T, Kawada T, Iwai K (1981) Formation and metabolism of pungent principle of Capsicum fruits. 9. Biosynthesis of acyl moieties of capsaicin and its analogs from valine and leucine in Capsicum fruits. Plant Cell Physiol 22:23–32]
  23. ↑ [Curry J, Aluru M, Mendoza M, Nevarez J, Melendrez M, O’Connell MA (1999) Transcripts for possible capsaicinoid biosynthetic genes are differentially accumulated in pungent and non-pungent Capsicum spp. Plant Sci 148:47–57]
  24. ↑ Nelson EK, Dawson LE (1923). "Constitution of capsaicin, the pungent principle of Capsicum. III". J Am Chem Soc. 45: 2179–2181. doi:10.1021/ja01662a023.
  25. ↑ Stewart C, Kang BC, Liu K, et al. (June 2005). "The Pun1 gene for pungency in pepper encodes a putative acyltransferase". Plant J. 42 (5): 675–88. doi:10.1111/j.1365-313X.2005.02410.x. PMID 15918882.
  26. 1 2 3 Leete E, Louden MC (1968). "Biosynthesis of capsaicin and dihydrocapsaicin in Capsicum frutescens". J. Am. Chem. Soc. 90: 6837–6841. doi:10.1021/ja01026a049.
  27. 1 2 3 Bennett DJ, Kirby GW (1968). "Constitution and biosynthesis of capsaicin". J. Chem. Soc. C. 1968: 442–446.
  28. ↑ Fujiwake H.; Suzuki T.; Oka S.; Iwai K. (1980). "Enzymatic formation of capsaicinoid from vanillylamine and iso-type fatty acids by cell-free extracts of Capsicum annuum var. annuum cv. Karayatsubusa". Agricultural and Biological Chemistry. 44: 2907–2912. doi:10.1271/bbb1961.44.2907.
  29. ↑ I. Guzman, P.W. Bosland, and M.A. O'Connell, "Chapter 8: Heat, Color, and Flavor Compounds in Capsicum Fruit" in David R. Gang, ed., Recent Advances in Phytochemistry 41: The Biological Activity of Phytochemicals (New York, New York: Springer, 2011), pages 117-118.
  30. ↑ Kozukue N, Han JS, Kozukue E, Lee SJ, Kim JA, Lee KR, Levin CE, Friedman M (2005). "Analysis of eight capsaicinoids in peppers and pepper-containing foods by high-performance liquid chromatography and liquid chromatography-mass spectrometry". J Agric Food Chem. 53: 9172–9181. doi:10.1021/jf050469j.
  31. ↑ Thiele R, Mueller-Seitz E, Petz M (2008). "Chili pepper fruits: presumed precursors of fatty acids characteristic for capsaicinoids". J Agric Food Chem. 56: 4219–4224. doi:10.1021/jf073420h.
  32. ↑ New Mexico State University - College of Agriculture and Home Economics (2005). "Chile Information - Frequently Asked Questions". Archived from the original on 4 May 2007. Retrieved 17 May 2007.
  33. ↑ Tewksbury, J. J.; Nabhan, G. P. (2001). "Seed dispersal. Directed deterrence by capsaicin in chilies". Nature. 412 (6845): 403–404. doi:10.1038/35086653. PMID 11473305.
  34. ↑ Joshua J. Tewksbury; Karen M. Reagan; Noelle J. Machnicki; Tomás A. Carlo; David C. Haak; Alejandra Lorena Calderón Peñaloza; Douglas J. Levey (19 August 2008), "Evolutionary ecology of pungency in wild chilies", Proceedings of the National Academy of Sciences, 105 (33): 11808–11811, doi:10.1073/pnas.0802691105, retrieved 30 June 2010
  35. ↑ Siemens J, Zhou S, Piskorowski R, et al. (November 2006). "Spider toxins activate the capsaicin receptor to produce inflammatory pain". Nature. 444 (7116): 208–12. doi:10.1038/nature05285. PMID 17093448.
  36. 1 2 3 4 5 Gorman J (20 September 2010). "A Perk of Our Evolution: Pleasure in Pain of Chilies". New York Times. Retrieved 16 March 2015.
  37. 1 2 Rollyson WD, et al. (2014). "Bioavailability of capsaicin and its implications for drug delivery". J Control Release. 196: 96–105. doi:10.1016/j.jconrel.2014.09.027. PMID 25307998.
  38. 1 2 3 4 5 Fattori, V; Hohmann, M. S.; Rossaneis, A. C.; Pinho-Ribeiro, F. A.; Verri, W. A. (2016). "Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses". Molecules. 21 (7): 844. doi:10.3390/molecules21070844. PMID 27367653.
  39. ↑ "FDA Approves New Drug Treatment for Long-Term Pain Relief after Shingles Attacks". U.S. Food and Drug Administration. 17 November 2009. Retrieved 5 January 2016.
  40. ↑ Hitt E (9 March 2012). "FDA Turns Down Capsaicin Patch for Painful Neuropathy in HIV". Medscape Medical News, WebMD. Retrieved 5 January 2016.
  41. ↑ Glinski W, Glinska-Ferenz M, Pierozynska-Dubowska M (1991). "Neurogenic inflammation induced by capsaicin in patients with psoriasis.". Acta dermato-venereologica. Acta Derm Venereol. 71 (1): 51–4. PMID 1711752.
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