:Piperine

{{short description|Alkaloid responsible for the pungency of black pepper}}

{{chembox

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| verifiedrevid = 414843869

| ImageFile1 = piperin.svg

| ImageFile2 = Piperine_crystals.jpg

| ImageName = Octane-3D-balls.png

| PIN = (2E,4E)-5-(2H-1,3-Benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one

| OtherNames = (2E,4E)-5-(Benzo[d] [1,3]dioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one
Piperoylpiperidine
Bioperine

| Section1 = {{Chembox Identifiers

| IUPHAR_ligand = 2489

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 28821

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 43185

| CASNo = 94-62-2

| CASNo_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = U71XL721QK

| PubChem = 638024

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 553590

| SMILES = O=C(N1CCCCC1)\C=C\C=C\c2ccc3OCOc3c2

| InChI = 1/C17H19NO3/c19-17(18-10-4-1-5-11-18)7-3-2-6-14-8-9-15-16(12-14)21-13-20-15/h2-3,6-9,12H,1,4-5,10-11,13H2/b6-2+,7-3+

| InChIKey = MXXWOMGUGJBKIW-YPCIICBEBY

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C17H19NO3/c19-17(18-10-4-1-5-11-18)7-3-2-6-14-8-9-15-16(12-14)21-13-20-15/h2-3,6-9,12H,1,4-5,10-11,13H2/b6-2+,7-3+

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = MXXWOMGUGJBKIW-YPCIICBESA-N

}}

| Section2 = {{Chembox Properties

| C=17|H=19|N=1|O=3

| Density = 1.193 g/cm³

| MeltingPtC = 130

| BoilingPt = Decomposes

| pKa =

| Solubility = 40{{nbsp}}mg/l

| Solvent1 = ethanol

| Solubility1 = soluble

| Solvent2 = chloroform

| Solubility2 = 1{{nbsp}}g/1.7{{nbsp}}ml

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| Section3 = {{Chembox Hazards

| ExternalSDS = [https://fscimage.fishersci.com/msds/04545.htm MSDS for piperine] }}

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{{Infobox pepper

| scoville = 150,000{{Cite book|url=https://books.google.com/books?id=2UQ8BAAAQBAJ|title=Pharmacognosy: An Indian perspective|last=Mangathayaru|first=K.|date=2013|publisher=Pearson Education India|isbn=9789332520264|pages=274|language=en}}

}}

Piperine, possibly along with its isomer chavicine, is the compound{{Merck11th|page=7442}} responsible for the pungency of black pepper and long pepper via activation of TRPV1.{{cite journal |last1=Dong |first1=Y |last2=Yin |first2=Y |last3=Vu |first3=S |last4=Yang |first4=F |last5=Yarov-Yarovoy |first5=V |last6=Tian |first6=Y |last7=Zheng |first7=J |title=A distinct structural mechanism underlies TRPV1 activation by piperine. |journal=Biochemical and Biophysical Research Communications |date=20 August 2019 |volume=516 |issue=2 |pages=365–372 |doi=10.1016/j.bbrc.2019.06.039 |pmid=31213294|pmc=6626684 }} It has been used in some forms of traditional medicine.{{cite journal |title=Black pepper and its pungent principle-piperine: A review of diverse physiological effects

|author=Srinivasan, K.|doi=10.1080/10408390601062054|journal=Critical Reviews in Food Science and Nutrition|volume=47|year=2007|issue=8|pages=735–748|pmid=17987447|s2cid=42908718}}

Preparation

=== Extraction ===

Due to its poor solubility in water, piperine is typically extracted from black pepper by using organic solvents like dichloromethane{{cite journal | title = Isolation of Piperine from Black Pepper | last1 = Epstein | first1 = William W. | last2 = Netz | first2 = David F. | last3 = Seidel | first3 = Jimmy L. | year = 1993 | volume = 70 | pages = 598 | journal = J. Chem. Educ. | doi = 10.1021/ed070p598 | issue = 7| bibcode = 1993JChEd..70..598E }} or ethanol.{{cite journal |last1=Chen∗ |first1=Zhe |last2=Wu∗ |first2=Jian Bing |last3=Zhang |first3=Jie |last4=Li |first4=Xiao Juan |last5=Shen |first5=Min He |title=One Step Purification of Piperine Directly from Piper nigrum L. by High Performance Centrifugal Partition Chromatography |journal=Separation Science and Technology |date=2 June 2009 |volume=44 |issue=8 |pages=1884–1893 |doi=10.1080/01496390902775877}} The amount of piperine varies from 1–2% in long pepper, to 5–10% in commercial white and black peppers.{{cite web|url=http://www.tis-gdv.de/tis_e/ware/gewuerze/pfeffer/pfeffer.htm#selbsterhitzung|title=Pepper|website=Tis-gdv.de|access-date=2 September 2017}}{{cite book |last=Henry |first=Thomas Anderson |title=The Plant Alkaloids |date=1949 |publisher=The Blakiston Company |isbn= |edition=4th |location= |pages=35–37 |section=Piperine}}

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). 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.{{cite book|last=Ikan|first=Raphael | title = Natural Products: A Laboratory Guide |edition=2nd |year=1991|publisher=Academic Press|location=San Diego, CA|isbn=0123705517|pages=223–224|url=https://books.google.com/books?id=B7P8HQimBAIC&q=Natural+Products%3A+A+Laboratory+Guide+2nd+Ed.}}

= Chemical synthesis =

Piperine has been synthesized by the action of piperonoyl chloride on piperidine.

= Biosynthesis =

The biosynthesis of piperine is only partially known.{{cite journal |last1=Schnabel |first1=Arianne |last2=Athmer |first2=Benedikt |last3=Manke |first3=Kerstin |last4=Schumacher |first4=Frank |last5=Cotinguiba |first5=Fernando |last6=Vogt |first6=Thomas |title=Identification and characterization of piperine synthase from black pepper, Piper nigrum L. |journal=Communications Biology |date=8 April 2021 |volume=4 |issue=1 |page=445 |doi=10.1038/s42003-021-01967-9|pmid=33833371 |pmc=8032705 }}

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 {{cite journal |last1=Vargas-Huertas |first1=Luis Felipe |last2=Alvarado-Corella |first2=Luis Diego |last3=Sánchez-Kopper |first3=Andrés |last4=Araya-Sibaja |first4=Andrea Mariela |last5=Navarro-Hoyos |first5=Mirtha |title=Characterization and Isolation of Piperamides from Piper nigrum Cultivated in Costa Rica |journal=Horticulturae |date=9 December 2023 |volume=9 |issue=12 |pages=1323 |doi=10.3390/horticulturae9121323|doi-access=free }}) besides piperine found in black pepper. Both enzymes are BAHD acyltransferases.

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.

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

In light, especially ultraviolet light, piperine is changed into its isomers chavicine, isochavicine and isopiperine, which are tasteless.{{cite journal |last1=Kozukue |first1=Nobuyuki |last2=Park |first2=Mal-Sun |last3=others |first3=and 5 |title=Kinetics of Light-Induced Cis−Trans Isomerization of Four Piperines and Their Levels in Ground Black Peppers as Determined by HPLC and LC/MS |journal=J. Agric. Food Chem. |date=2007 |volume=55 |issue=17 |pages=7131–7139 |doi=10.1021/jf070831p |pmid=17661483 |bibcode=2007JAFC...55.7131K |url=https://doi.org/10.1021/jf070831p |access-date=26 September 2023|url-access=subscription }}{{cite journal |last1=De Cleyn |first1=R |last2=Verzele |first2=M |title=Constituents of peppers. I Qualitative Analysis of Piperine Isomers |journal=Chromatografia |date=1972 |volume=5 |pages=346–350 |doi=10.1007/BF02315254 |s2cid=56022338 |url=https://www.chm.bris.ac.uk/sillymolecules/chavicine.pdf |access-date=26 September 2023}}

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.{{cite journal|last=Ørsted |first=Hans Christian |author-link=Hans Christian Ørsted |url=https://books.google.com/books?id=k-M4AAAAMAAJ&pg=PA80 |title=Über das Piperin, ein neues Pflanzenalkaloid|language=de |trans-title=On piperine, a new plant alkaloid |journal=Schweiggers Journal für Chemie und Physik |volume= 29 |issue= 1 |pages=80–82 |date=1820}} Piperine was also found in Piper longum and Piper officinarum (Miq.) C. DC. (=Piper retrofractum Vahl), two species called "long pepper".{{cite book|title=Pharmacographia : a History of the Principal Drugs of Vegetable Origin, Met with in Great Britain and British India|url=https://archive.org/details/pharmacographia01hanbgoog|author1=Friedrich A. Fluckiger|author2=Daniel Hanbury|location=London|publisher=Macmillan|date=1879|page=[https://archive.org/details/pharmacographia01hanbgoog/page/n595 584]|asin=B00432KEP2}}

Uses

Piperine is widely used in the supplements industry for its effect on enhancing absorption and bioavailability of other compounds such as curcumin,{{cite journal |last1=Hewlings |first1=Susan |last2=Kalman |first2=Douglas |title=Curcumin: A Review of Its' Effects on Human Health |journal=Foods |date=2017 |volume=6 |issue=10 |page=92 |doi=10.3390/foods6100092 |doi-access=free |pmid=29065496 |pmc=5664031 }} 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,{{cite journal |last1=Chopra |first1=Bhawna |last2=Dhingra |first2=Ashwani |title=Piperine and Its Various Physicochemical and Biological Aspects: A Review |journal=Open Chemistry Journal |date=2016 |volume=3 |pages=75–96 |doi=10.2174/1874842201603010075 |url=https://www.researchgate.net/publication/312034352 |access-date=7 May 2025|doi-access=free }} UDP-glucose 6-dehydrogenase, and glucuronosyltransferase.{{cite journal |last1=Reen |first1=RK |last2=Jamwal |first2=DS |last3=Taneja |first3=SC |last4=Koul |first4=JL |last5=Dubey |first5=RK |last6=Wiebel |first6=FJ |last7=Singh |first7=J |title=Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small intestine of rat and guinea pig in vitro by piperine. |journal=Biochemical Pharmacology |date=20 July 1993 |volume=46 |issue=2 |pages=229–38 |doi=10.1016/0006-2952(93)90408-o |pmid=8347144}} The last two activities (inhibition of glucuronidation) are most relevant for curcumin.{{cite journal |last1=Anand |first1=Preetha |last2=Kunnumakkara |first2=Ajaikumar B. |last3=Newman |first3=Robert A. |last4=Aggarwal |first4=Bharat B. |title=Bioavailability of Curcumin: Problems and Promises |journal=Molecular Pharmaceutics |date=1 December 2007 |volume=4 |issue=6 |pages=807–818 |doi=10.1021/mp700113r|pmid=17999464 }}