Kavalactone

{{Short description|Group of chemical compounds}} 300px|thumb|right|The general structure of the kavalactones, without the R1-R2 -O-CH2-O- bridge and with all possible C=C double bonds shown. '''Kavalactones''' are a class of lactone compounds found in kava roots and ''Alpinia zerumbet'' (shell ginger)<ref name=Syn>{{cite journal |doi=10.1055/s-0040-1706044 |title=A Review on Synthetic Approaches towards Kavalactones |date=2021 |last1=Tadiparthi |first1=Krishnaji |last2=Anand |first2=Pragya |journal=Synthesis |volume=53 |issue=19 |pages=3469–3484 |s2cid=236392304 }}</ref> and in several Gymnopilus, Phellinus and Inonotus fungi.<ref>{{cite journal | last1=Hatfield | first1=G. M. | last2=Brady | first2=L. R. | title=Occurrence of bis-noryangonin in Gymnopilus spectabilis | journal=Journal of Pharmaceutical Sciences | date=1969 | volume=58 | issue=10 | pages=1298–1299 | doi=10.1002/jps.2600581039 | pmid=5388695 | bibcode=1969JPhmS..58.1298H | url=https://jpharmsci.org/article/S0022-3549(15)37017-9/abstract }}</ref> Some kavalactones are bioactive. They are responsible for the psychoactive, analgesic, euphoric and sedative effects of kava.<ref name="tandfonline.com">{{Cite journal | url=https://www.tandfonline.com/doi/abs/10.1080/14786419.2021.2023866?journalCode=gnpl20 | doi=10.1080/14786419.2021.2023866 | title=Kavalactones isolated from Alpinia zerumbet (Pers.) Burtt. Et Smith with protective effects against human umbilical vein endothelial cell damage induced by high glucose | year=2022 | last1=You | first1=Hualin | last2=He | first2=Min | last3=Pan | first3=Di | last4=Fang | first4=Guanqin | last5=Chen | first5=Yan | last6=Zhang | first6=Xu | last7=Shen | first7=Xiangchun | last8=Zhang | first8=Nenling | journal=Natural Product Research | volume=36 | issue=22 | pages=5740–5746 | pmid=34989299 | s2cid=245771677 | url-access=subscription }}</ref><ref>{{cite journal|title=Inhibition of Human Cytochrome P450 Activities by Kava Extract and Kavalactones|journal=Drug Metabolism and Disposition |volume=30 |issue=11 |pages=1153–1157 |author1=James M. Mathews |author2=Amy S. Etheridge |author3=Sherry R. Black |url=http://dmd.aspetjournals.org/content/30/11/1153.short|doi=10.1124/dmd.30.11.1153 |year=2002 |pmid=12386118 |url-access=subscription }}</ref>

==Bioactivity== Kava extract interacts with many pharmaceuticals and herbal medications. In human volunteers, in vivo inhibition includes CYP1A2<ref>{{Cite journal |last1=Russmann |first1=S |last2=Lauterburg |first2=B |last3=Barguil |first3=Y |last4=Choblet |first4=E |last5=Cabalion |first5=P |last6=Rentsch |first6=K |last7=Wenk |first7=M |date=2005 |title=Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: Protective effect against environmental carcinogens? |url=http://doi.wiley.com/10.1016/j.clpt.2005.01.021 |journal=Clinical Pharmacology & Therapeutics |language=en |volume=77 |issue=5 |pages=453–454 |doi=10.1016/j.clpt.2005.01.021|pmid=15900292 |s2cid=36009940 |url-access=subscription }}</ref> and CYP2E1<ref>{{Cite journal |last1=Gurley |first1=B |last2=Gardner |first2=S |last3=Hubbard |first3=M |last4=Williams |first4=D |last5=Gentry |first5=W |last6=Khan |first6=I |last7=Shah |first7=A |date=2005 |title=In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes |journal=Clinical Pharmacology & Therapeutics |language=en |volume=77 |issue=5 |pages=415–426 |doi=10.1016/j.clpt.2005.01.009 |pmc=1894911 |pmid=15900287}}</ref> through use of probe drugs to measure inhibition.

== Research == Its anxiolytic and hepatotoxic properties have been investigated.<ref name=":0">{{Cite journal|last1=Sarris|first1=Jerome|last2=LaPorte|first2=Emma|last3=Schweitzer|first3=Isaac|date=2011-01-01|title=Kava: A Comprehensive Review of Efficacy, Safety, and Psychopharmacology|journal=Australian & New Zealand Journal of Psychiatry|language=en|volume=45|issue=1|pages=27–35|doi=10.3109/00048674.2010.522554|pmid=21073405|s2cid=42935399}}</ref><ref name="teschke">{{cite journal|pmid=21756963|year=2011|last1=Teschke|first1=R|title=Proposal for a kava quality standardization code|journal=Food and Chemical Toxicology|volume=49|issue=10|pages=2503–16|last2=Lebot|first2=V|doi=10.1016/j.fct.2011.06.075}}</ref><ref>{{cite journal|pmc=4325077|year=2013|last1=Wang|first1=J|title=Kavalactone content and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varieties and extraction efficiency of kavalactones using different solvents|journal=Journal of Food Science and Technology|volume=52|issue=2|pages=1164–1169|last2=Qu|first2=W|last3=Bittenbender|first3=H. C.|last4=Li|first4=Q. X.|doi=10.1007/s13197-013-1047-2|pmid=25694734}}</ref>

The major kavalactones (except for des{{shy}}methoxy{{shy}}yangonin) potentiate GABAA receptors, which may underlie the anxiolytic and sedative properties of kava. Further, inhibition of the reuptake of nor{{shy}}epi{{shy}}neph{{shy}}rine and dopamine, binding to the CB1 receptor,<ref name="pmid22525682">{{cite journal | vauthors = Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V | title = Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand | journal = Pharmacol. Res. | volume = 66 | issue = 2 | pages = 163–9 | year = 2012 | pmid = 22525682 | doi = 10.1016/j.phrs.2012.04.003 }}</ref> inhibition of voltage-gated sodium and calcium channels, and monoamine oxidase B reversible inhibition are additional pharmacological actions that have been reported for kavalactones.<ref name="pmid12383029">{{cite journal | vauthors = Singh YN, Singh NN | title = Therapeutic potential of kava in the treatment of anxiety disorders | journal = CNS Drugs | volume = 16 | issue = 11 | pages = 731–43 | year = 2002 | pmid = 12383029 | doi = 10.2165/00023210-200216110-00002| s2cid = 34322458 }}</ref>

==Toxicity== Several kavalactones (e.g., methysticin and yangonin) affect a group of enzymes involved in metabolism, called the CYP450 system. Hepatotoxicity occurred in a small portion of previously healthy kava users,<ref name=teschke/><ref name="teschke2">{{cite journal|pmid=21442674|year=2011|last1=Teschke|first1=R|title=Kava and kava hepatotoxicity: Requirements for novel experimental, ethnobotanical and clinical studies based on a review of the evidence|journal=Phytotherapy Research|volume=25|issue=9|pages=1263–74|last2=Qiu|first2=S. X.|last3=Xuan|first3=T. D.|last4=Lebot|first4=V|doi=10.1002/ptr.3464|s2cid=19142750}}</ref> particularly from extracts, as opposed to whole root powders.

== Compounds == {{see also|Flavokavain}} At least 18 different kavalactones are known,<ref name=Syn/> with methysticin being the first identified.<ref> {{ cite journal | last1 = Naumov | first1 = P. | last2 = Dragull | first2 = K. | last3 = Yoshioka | first3 = M. | last4 = Tang | first4 = C.-S. | last5 = Ng | first5 = S. W. | title = Structural Characterization of Genuine (-)-Pipermethystine, (-)-Epoxypipermethystine, (+)-Dihydromethysticin and Yangonin from the Kava Plant (Piper methysticum) | url = http://www.naturalproduct.us/ | journal = Natural Product Communications | year = 2008 | volume = 3 | issue = 8 | pages = 1333–1336 | doi = 10.1177/1934578X0800300819 | s2cid = 92030132 | doi-access= free | url-access= subscription }} </ref> Multiple analogues, such as ethysticin, have also been isolated.<ref> {{cite journal | last = Shulgin | first = A. | title = The narcotic pepper - the chemistry and pharmacology of Piper methysticum and related species | journal = Bulletin on Narcotics | issue = 2 | year = 1973 | pages = 59–74 | url = http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1973-01-01_2_page008.html }}</ref> Some consist of a substituted α-pyrone as the lactone, while others are partially saturated.

The average elimination half-life of kavalactones typically present in kava root is 9 hr.<ref>{{cite web|url=http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler/piper-methysticum.html|title=Kava (''Piper methysticum''): Pharmacodynamics/Kinetics|publisher=Sigma-Aldrich Co. LLC|date=2010}}</ref>

{| class="wikitable" |+ '''Kavalactones''' |- ! Name ! Structure ! R1 ! R2 ! R3 ! R4 |- | Yangonin | align="center" | 1 | -OCH3 | -H | -H | -H |- | 10-methoxyyangonin | align="center" | 1 | -OCH3 | -H | -OCH3 | -H |- | 11-methoxyyangonin | align="center" | 1 | -OCH3 | -OCH3 | -H | -H |- | 11-hydroxyyangonin | align="center" | 1 | -OCH3 | -OH | -H | -H |- | Desmethoxyyangonin | align="center" | 1 | -H | -H | -H | -H |- | 11-methoxy-12-hydroxydehydrokavain | align="center" | 1 | -OH | -OCH3 | -H | -H |- | 7,8-dihydroyangonin | align="center" | 2 | -OCH3 | -H | -H | -H |- | Kavain | align="center" | 3 | -H | -H | -H | -H |- | 5-hydroxykavain | align="center" | 3 | -H | -H | -H | -OH |- | 5,6-dihydroyangonin | align="center" | 3 | -OCH3 | -H | -H | -H |- | 7,8-dihydrokavain | align="center" | 4 | -H | -H | -H | -H |- | 5,6,7,8-tetrahydroyangonin | align="center" | 4 | -OCH3 | -H | -H | -H |- | 5,6-dehydromethysticin | align="center" | 5 | align="center" colspan="2" | -O-CH2-O- | -H | -H |- | Methysticin | align="center" | 7 | align="center" colspan="2" | -O-CH2-O- | -H | -H |- | 7,8-dihydromethysticin | align="center" | 8 | align="center" colspan="2" | -O-CH2-O- | -H | -H |}

==Biosynthesis== The kavalactone biosynthetic pathway in ''Piper methysticum'' was described in 2019.<ref name="Pluskal Torrens-Spence Fallon De Abreu pp. 867–878">{{cite journal | last1=Pluskal | first1=Tomáš | last2=Torrens-Spence | first2=Michael P. | last3=Fallon | first3=Timothy R. | last4=De Abreu | first4=Andrea | last5=Shi | first5=Cindy H. | last6=Weng | first6=Jing-Ke | title=The biosynthetic origin of psychoactive kavalactones in kava | journal=Nature Plants | publisher=Springer Science and Business Media LLC | volume=5 | issue=8 | date=2019-07-22 | issn=2055-0278 | doi=10.1038/s41477-019-0474-0 | pages=867–878| pmid=31332312 | bibcode=2019NatPl...5..867P | hdl=1721.1/124692 | s2cid=198139136 | hdl-access=free }}</ref>

==See also== * Pipermethystine

==References== {{reflist|30em}}

==External links== * {{ cite web | url = http://www.erowid.org/plants/kava/kava_chemistry2.shtml | title = NIH Kava Chemistry & Toxicology, Executive Summary }} *[https://www.theguardian.com/world/2020/feb/05/the-great-kava-boom-how-fijis-beloved-psychoactive-brew-is-going-global The great kava boom: how Fiji's beloved psychoactive brew is going global] The Guardian, 2020

Category:Monoamine oxidase inhibitors Category:Kavalactones Category:GABAA receptor positive allosteric modulators Category:Anxiolytics Category:Analgesics Category:Sedatives Category:Anticonvulsants Category:Nootropics