Piperine

Piperine, possibly along with its isomer chavicine,[1] is the compound[2] responsible for the pungency of black pepper and long pepper via activation of TRPV1.[3] It has been used in some forms of traditional medicine.[4]

## Contents

* 1 Preparation
* 1.1 Extraction
* 1.2 Chemical synthesis
* 1.3 Biosynthesis
* 2 Reactions
* 3 History
* 4 Uses
* 5 See also
* 6 References

## Preparation

### Extraction

Due to its poor solubility in water, piperine is typically extracted from black pepper by using organic solvents like dichloromethane[5] or ethanol.[6] The amount of piperine varies from 1–2% in long pepper, to 5–10% in commercial white and black peppers.[7][8]

Piperine can also be prepared by treating the solvent-free residue from a concentrated alcoholic extract of black pepper with a solution of potassium hydroxide to remove resin (said to contain chavicine, an isomer of piperine).[8] The solution is decanted from the insoluble residue and left to stand overnight in alcohol. During this period, the alkaloid slowly crystallizes from the solution.[9]

### Chemical synthesis

Piperine has been synthesized by the reaction of piperonoyl chloride with piperidine.[8]

### Biosynthesis

The biosynthesis of piperine is only partially known.[10]

* The last step is catalyzed by piperine synthase (piperoyl-CoA:piperidine piperoyl transferase). As suggested by its systematic name, it converts piperoyl-CoA and piperidine into piperine.
* Piperoyl-CoA is made by piperoyl-CoA ligase from piperic acid, which is in turn made from feruperic acid by CYP719A37.
* Feruperic acid is presumably made from ferulic acid. Piperine is presumably made from lysine.

In addition to piperine synthase PipBAHD2, there is an orthologous enzyme with broader substract specificity in Piper nigrum with gene symbol PipBAHD1, called a "piperamide synthase". This other enzyme is responsible for the many piperamide compounds (see [11]) besides piperine found in black pepper. Both enzymes are BAHD acyltransferases.[10]

## Reactions

Piperine forms salts only with strong acids. The platinichloride B4·H2PtCl6 forms orange-red needles ("B" denotes one mole of the alkaloid base in this and the following formula). Iodine in potassium iodide added to an alcoholic solution of the base in the presence of a little hydrochloric acid gives a characteristic periodide, B2·HI·I2, crystallizing in steel-blue needles with melting point 145 °C.[8]

Piperine can be hydrolyzed by an alkali into piperidine and piperic acid.[8]

In light, especially ultraviolet light, piperine is changed into its isomers chavicine, isochavicine and isopiperine, which are tasteless.[12][1]

## History

Piperine was discovered in 1819 by Hans Christian Ørsted, who isolated it from the fruits of Piper nigrum, the source plant of both black and white pepper.[13] Piperine was also found in Piper longum and Piper officinarum (Miq.) C. DC. (=Piper retrofractum Vahl), two species called "long pepper".[14]

## Uses

Piperine is widely used in the supplements industry for its effect on enhancing absorption and bioavailability of other compounds such as curcumin,[15] resveratrol, ashwaganda, amino acids, vitamins and several minerals including selenium. It has been reported to inhibit several enzymes that participate in xenobiotic metabolism, including CYP3A4, P-gp,[16] UDP-glucose 6-dehydrogenase, and glucuronosyltransferase.[17] The last two activities (inhibition of glucuronidation) are most relevant for curcumin.[18]

## See also

* Piperidine, a cyclic six-membered amine that results from hydrolysis of piperine
* Piperic acid, the carboxylic acid also derived from hydrolysis of piperine
* Capsaicin, the active piquant chemical in chili peppers
* Allyl isothiocyanate, the active piquant chemical in mustard, radishes, horseradish, and wasabi
* Allicin, the active piquant flavor chemical in raw garlic and onions (see those articles for discussion of other chemicals in them relating to pungency, and eye irritation)
* Ilepcimide
* Piperlongumine

## References

1. ↑ 1.0 1.1 De Cleyn, R; Verzele, M (1972). "Constituents of peppers. I Qualitative Analysis of Piperine Isomers". Chromatografia 5: 346–350. doi:10.1007/BF02315254. https://www.chm.bris.ac.uk/sillymolecules/chavicine.pdf. Retrieved 26 September 2023.
2. ↑ An Encyclopedia of Chemicals, Drugs, and Biologicals (11th ed.), Merck, 1989, p. 7442, ISBN 091191028X
3. ↑ Dong, Y; Yin, Y; Vu, S; Yang, F; Yarov-Yarovoy, V; Tian, Y; Zheng, J (20 August 2019). "A distinct structural mechanism underlies TRPV1 activation by piperine.". Biochemical and Biophysical Research Communications 516 (2): 365–372. doi:10.1016/j.bbrc.2019.06.039. PMID 31213294. Bibcode: 2019BBRC..516..365D.
4. ↑ Srinivasan, K. (2007). "Black pepper and its pungent principle-piperine: A review of diverse physiological effects". Critical Reviews in Food Science and Nutrition 47 (8): 735–748. doi:10.1080/10408390601062054. PMID 17987447.
5. ↑ Epstein, William W.; Netz, David F.; Seidel, Jimmy L. (1993). "Isolation of Piperine from Black Pepper". J. Chem. Educ. 70 (7): 598. doi:10.1021/ed070p598. Bibcode: 1993JChEd..70..598E.
6. ↑ Chen∗, Zhe; Wu∗, Jian Bing; Zhang, Jie; Li, Xiao Juan; Shen, Min He (2 June 2009). "One Step Purification of Piperine Directly from Piper nigrum L. by High Performance Centrifugal Partition Chromatography". Separation Science and Technology 44 (8): 1884–1893. doi:10.1080/01496390902775877.
7. ↑ "Pepper". http://www.tis-gdv.de/tis_e/ware/gewuerze/pfeffer/pfeffer.htm#selbsterhitzung.
8. ↑ 8.0 8.1 8.2 8.3 8.4 Henry, Thomas Anderson (1949). The Plant Alkaloids (4th ed.). The Blakiston Company. pp. 35–37.
9. ↑ Ikan, Raphael (1991). Natural Products: A Laboratory Guide (2nd ed.). San Diego, CA: Academic Press. pp. 223–224. ISBN 0123705517. https://books.google.com/books?id=B7P8HQimBAIC&q=Natural+Products:+A+Laboratory+Guide+2nd+Ed..
10. ↑ 10.0 10.1 Schnabel, Arianne; Athmer, Benedikt; Manke, Kerstin; Schumacher, Frank; Cotinguiba, Fernando; Vogt, Thomas (8 April 2021). "Identification and characterization of piperine synthase from black pepper, Piper nigrum L.". Communications Biology 4 (1): 445. doi:10.1038/s42003-021-01967-9. PMID 33833371.
11. ↑ Vargas-Huertas, Luis Felipe; Alvarado-Corella, Luis Diego; Sánchez-Kopper, Andrés; Araya-Sibaja, Andrea Mariela; Navarro-Hoyos, Mirtha (9 December 2023). "Characterization and Isolation of Piperamides from Piper nigrum Cultivated in Costa Rica". Horticulturae 9 (12): 1323. doi:10.3390/horticulturae9121323.
12. ↑ Kozukue, Nobuyuki; Park, Mal-Sun; others, and 5 (2007). "Kinetics of Light-Induced Cis−Trans Isomerization of Four Piperines and Their Levels in Ground Black Peppers as Determined by HPLC and LC/MS". J. Agric. Food Chem. 55 (17): 7131–7139. doi:10.1021/jf070831p. PMID 17661483. Bibcode: 2007JAFC...55.7131K. https://doi.org/10.1021/jf070831p. Retrieved 26 September 2023.
13. ↑ Ørsted, Hans Christian (1820). "Über das Piperin, ein neues Pflanzenalkaloid" (in de). Schweiggers Journal für Chemie und Physik 29 (1): 80–82. https://books.google.com/books?id=k-M4AAAAMAAJ&pg=PA80.
14. ↑ Friedrich A. Fluckiger; Daniel Hanbury (1879). Pharmacographia : a History of the Principal Drugs of Vegetable Origin, Met with in Great Britain and British India. London: Macmillan. p. 584. https://archive.org/details/pharmacographia01hanbgoog.
15. ↑ Hewlings, Susan; Kalman, Douglas (2017). "Curcumin: A Review of Its' Effects on Human Health". Foods 6 (10): 92. doi:10.3390/foods6100092. PMID 29065496.
16. ↑ Chopra, Bhawna; Dhingra, Ashwani (2016). "Piperine and Its Various Physicochemical and Biological Aspects: A Review". Open Chemistry Journal 3: 75–96. doi:10.2174/1874842201603010075. https://www.researchgate.net/publication/312034352. Retrieved 7 May 2025.
17. ↑ Reen, RK; Jamwal, DS; Taneja, SC; Koul, JL; Dubey, RK; Wiebel, FJ; Singh, J (20 July 1993). "Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small intestine of rat and guinea pig in vitro by piperine.". Biochemical Pharmacology 46 (2): 229–38. doi:10.1016/0006-2952(93)90408-o. PMID 8347144.
18. ↑ Anand, Preetha; Kunnumakkara, Ajaikumar B.; Newman, Robert A.; Aggarwal, Bharat B. (1 December 2007). "Bioavailability of Curcumin: Problems and Promises". Molecular Pharmaceutics 4 (6): 807–818. doi:10.1021/mp700113r. PMID 17999464.

* v
* t
* e

TRP channel modulators

TRPA|

| Activators|

* 4-Hydroxynonenal
* 4-Oxo-2-nonenal
* 4,5-EET
* 12S-HpETE
* 15-Deoxy-Δ12,14-prostaglandin J2
* α-Sanshool (ginger, Sichuan and melegueta peppers)
* Acrolein
* Allicin (garlic)
* Allyl isothiocyanate (mustard, radish, horseradish, wasabi)
* AM404
* Bradykinin
* Cannabichromene (cannabis)
* Cannabidiol (cannabis)
* Cannabigerol (cannabis)
* Cinnamaldehyde (cinnamon)
* CR gas (dibenzoxazepine; DBO)
* CS gas (2-chlorobenzal malononitrile)
* Curcumin (turmeric)
* Dehydroligustilide (celery)
* Diallyl disulfide
* Dicentrine (Lindera spp.)
* Farnesyl thiosalicylic acid
* Formalin
* Gingerols (ginger)
* Hepoxilin A3
* Hepoxilin B3
* Hydrogen peroxide
* Icilin
* Isothiocyanate
* Ligustilide (celery, Angelica acutiloba)
* Linalool (Sichuan pepper, thyme)
* Methylglyoxal
* Methyl salicylate (wintergreen)
* N-Methylmaleimide
* Nicotine (tobacco)
* Oleocanthal (olive oil)
* Paclitaxel (Pacific yew)
* Paracetamol (acetaminophen)
* PF-4840154
* Phenacyl chloride
* Polygodial (Dorrigo pepper)
* Shogaols (ginger, Sichuan and melegueta peppers)
* Tear gases
* Tetrahydrocannabinol (cannabis)
* Thiopropanal S-oxide (onion)
* Umbellulone (Umbellularia californica)
* WIN 55,212-2

|

Blockers|

* Dehydroligustilide (celery)
* Nicotine (tobacco)
* Ruthenium red

TRPC|

| Activators|

* Adhyperforin (St John's wort)
* Diacyl glycerol
* GSK1702934A
* Hyperforin (St John's wort)
* Substance P

|

Blockers|

* DCDPC
* DHEA-S
* Flufenamic acid
* GSK417651A
* GSK2293017A
* Meclofenamic acid
* N-(p-Amylcinnamoyl)anthranilic acid
* Niflumic acid
* Pregnenolone sulfate
* Progesterone
* Pyr3
* Tolfenamic acid

TRPM|

| Activators|

* ADP-ribose
* BCTC
* Calcium (intracellular)
* Cold
* Coolact P
* Cooling Agent 10
* CPS-369
* Eucalyptol (eucalyptus)
* Frescolat MGA
* Frescolat ML
* Geraniol
* Hydroxycitronellal
* Icilin
* Linalool
* Menthol (mint)
* PMD 38
* Pregnenolone sulfate
* Rutamarin (Ruta graveolens)
* Steviol glycosides (e.g., stevioside) (Stevia rebaudiana)
* Sweet tastants (e.g., glucose, fructose, sucrose; indirectly)
* Thio-BCTC
* WS-3
* WS-12
* WS-23

|

Blockers|

* Capsazepine
* Clotrimazole
* DCDPC
* Elismetrep
* Flufenamic acid
* Meclofenamic acid
* Mefenamic acid
* N-(p-Amylcinnamoyl)anthranilic acid
* Nicotine (tobacco)
* Niflumic acid
* Ruthenium red
* Rutamarin (Ruta graveolens)
* Tolfenamic acid
* TPPO

TRPML|

| Activators|

* MK6-83
* PI(3,5)P2
* SF-22

|

TRPP|

| Activators|

* Triptolide (Tripterygium wilfordii)

|

Blockers|

* Ruthenium red

TRPV|

| Activators|

* 2-APB
* 5',6'-EET
* 9-HODE
* 9-oxoODE
* 12S-HETE
* 12S-HpETE
* 13-HODE
* 13-oxoODE
* 20-HETE
* α-Sanshool (ginger, Sichuan and melegueta peppers)
* Allicin (garlic)
* AM404
* Anandamide
* Bisandrographolide (Andrographis paniculata)
* Camphor (camphor laurel, rosemary, camphorweed, African blue basil, camphor basil)<!--TRPV1 and TRPV3-->
* Cannabidiol (cannabis)
* Cannabidivarin (cannabis)
* Capsaicin (chili pepper)
* Carvacrol (oregano, thyme, pepperwort, wild bergamot, others)
* DHEA
* Diacyl glycerol
* Dihydrocapsaicin (chili pepper)
* Estradiol
* Eugenol (basil, clove)
* Evodiamine (Euodia ruticarpa)
* Gingerols (ginger)
* GSK1016790A
* Heat
* Hepoxilin A3
* Hepoxilin B3
* Homocapsaicin (chili pepper)
* Homodihydrocapsaicin (chili pepper)
* Incensole (incense)
* Lysophosphatidic acid
* Low pH (acidic conditions)
* Menthol (mint)
* N-Arachidonoyl dopamine
* N-Oleoyldopamine
* N-Oleoylethanolamide
* Nonivamide (PAVA) (PAVA spray)
* Nordihydrocapsaicin (chili pepper)
* Paclitaxel (Pacific yew)
* Paracetamol (acetaminophen)
* Phorbol esters (e.g., 4α-PDD)
* Piperine (black pepper, long pepper)
* Polygodial (Dorrigo pepper)
* Probenecid
* Protons
* RhTx
* Rutamarin (Ruta graveolens)
* Resiniferatoxin (RTX) (Euphorbia resinifera/pooissonii)
* Shogaols (ginger, Sichuan and melegueta peppers)
* Tetrahydrocannabivarin (cannabis)
* Thymol (thyme, oregano)
* Tinyatoxin (Euphorbia resinifera/pooissonii)
* Tramadol
* Vanillin (vanilla)
* Zucapsaicin

|

Blockers|

* α-Spinasterol (Vernonia tweediana)
* AMG-517
* Asivatrep
* BCTC
* Cannabigerol (cannabis)
* Cannabigerolic acid (cannabis)
* Cannabigerovarin (cannabis)
* Cannabinol (cannabis)
* Capsazepine
* DCDPC
* DHEA
* DHEA-S
* Flufenamic acid
* GRC-6211
* HC-067047
* Lanthanum
* Mavatrep
* Meclofenamic acid
* N-(p-Amylcinnamoyl)anthranilic acid
* NGD-8243
* Niflumic acid
* Pregnenolone sulfate
* RN-1734
* RN-9893
* Ruthenium red
* SB-705498
* Tivanisiran
* Tolfenamic acid

See also: Receptor/signaling modulators • Ion channel modulators

* v
* t
* e

Xenobiotic-sensing receptor modulators

CAR|

* Agonists: 6,7-Dimethylesculetin
* Amiodarone
* Artemisinin
* Benfuracarb
* Carbamazepine
* Carvedilol
* Chlorpromazine
* Chrysin
* CITCO
* Clotrimazole
* Cyclophosphamide
* Cypermethrin
* DHEA (prasterone)
* Efavirenz
* Ellagic acid
* Griseofulvin
* Methoxychlor
* Mifepristone
* Nefazodone
* Nevirapine
* Nicardipine
* Octicizer
* Permethrin
* Phenobarbital
* Phenytoin
* Pregnanedione (5β-dihydroprogesterone)
* Reserpine
* TCPOBOP
* Telmisartan
* Tolnaftate
* Troglitazone
* Valproic acid

* Antagonists: 3,17β-Estradiol
* 3α-Androstanol
* 3α-Androstenol
* 3β-Androstanol
* 17-Androstanol
* AITC
* Ethinylestradiol
* Meclizine
* Nigramide J
* Okadaic acid
* PK-11195
* S-07662
* T-0901317

PXR|

* Agonists: 17α-Hydroxypregnenolone
* 17α-Hydroxyprogesterone
* Δ4-Androstenedione
* Δ5-Androstenediol
* Δ5-Androstenedione
* AA-861
* Allopregnanediol
* Allopregnanedione (5α-dihydroprogesterone)
* Allopregnanolone (brexanolone)
* Alpha-Lipoic acid
* Ambrisentan
* AMI-193
* Amlodipine besylate
* Antimycotics
* Artemisinin
* Aurothioglucose
* Bile acids
* Bithionol
* Bosentan
* Bumecaine
* Cafestol
* Cephaloridine
* Cephradine
* Chlorpromazine
* Ciglitazone
* Clindamycin
* Clofenvinfos
* Chloroxine
* Clotrimazole
* Colforsin
* Corticosterone
* Cyclophosphamide
* Cyproterone acetate
* Demecolcine
* Dexamethasone
* DHEA (prasterone)
* DHEA-S (prasterone sulfate)
* Dibunate sodium
* Diclazuril
* Dicloxacillin
* Dimercaprol
* Dinaline
* Docetaxel
* Docusate calcium
* Dodecylbenzenesulfonic acid
* Dronabinol
* Droxidopa
* Eburnamonine
* Ecopipam
* Enzacamene
* Epothilone B
* Erythromycin
* Famprofazone
* Febantel
* Felodipine
* Fenbendazole
* Fentanyl
* Flucloxacillin
* Fluorometholone
* Griseofulvin
* Guggulsterone
* Haloprogin
* Hetacillin potassium
* Hyperforin
* Hypericum perforatum (St John's wort)
* Indinavir sulfate
* Lasalocid sodium
* Levothyroxine
* Linolenic acid
* LOE-908
* Loratadine
* Lovastatin
* Meclizine
* Metacycline
* Methylprednisolone
* Metyrapone
* Mevastatin
* Mifepristone
* Nafcillin
* Nicardipine
* Nicotine
* Nifedipine
* Nilvadipine
* Nisoldipine
* Norelgestromin
* Omeprazole
* Orlistat
* Oxatomide
* Paclitaxel
* Phenobarbital
* Piperine
* Plicamycin
* Prednisolone
* Pregnanediol
* Pregnanedione (5β-dihydroprogesterone)
* Pregnanolone
* Pregnenolone
* Pregnenolone 16α-carbonitrile
* Proadifen
* Progesterone
* Quingestrone
* Reserpine
* Reverse triiodothyronine
* Rifampicin
* Rifaximin
* Rimexolone
* Riodipine
* Ritonavir
* Simvastatin
* Sirolimus
* Spironolactone
* Spiroxatrine
* SR-12813
* Suberoylanilide
* Sulfisoxazole
* Suramin
* Tacrolimus
* Tenylidone
* Terconazole
* Testosterone isocaproate
* Tetracycline
* Thiamylal sodium
* Thiothixene
* Thonzonium bromide
* Tianeptine
* Troglitazone
* Troleandomycin
* Tropanyl 3,5-dimethulbenzoate
* Zafirlukast
* Zeranol

* Antagonists: Ketoconazole
* Sesamin

See also
Receptor/signaling modulators
Nuclear receptor modulators

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*[TRP]: Transient receptor potential
*[TRPA]: Transient receptor potential ankyrin channel
*[TRPC]: Transient receptor potential canonical channel
*[TRPM]: Transient receptor potential melastatin channel
*[TRPML]: Transient receptor potential mucolipin channel
*[TRPP]: Transient receptor potential polycystin channel
*[TRPV]: Transient receptor potential vanilloid channel
*[CAR]: Constitutive androstane receptor
*[PXR]: Pregnane X receptor