kavalactone
{{Short description|Group of chemical compounds}}
Image:Kavalactone-general-numbered.svg
Kavalactones are a class of lactone compounds found in kava roots and Alpinia zerumbet (shell ginger){{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 }} and in several Gymnopilus, Phellinus and Inonotus fungi.https://jpharmsci.org/article/S0022-3549(15)37017-9/abstract Some kavalactones are bioactive. They are responsible for the psychoactive, analgesic, euphoric and sedative effects of kava.{{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 }}{{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 }}
Bioactivity
Kava extract interacts with many pharmaceuticals and herbal medications. In human volunteers, in vivo inhibition includes CYP1A2{{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 }} and CYP2E1{{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}} through use of probe drugs to measure inhibition.
Research
Its anxiolytic and hepatotoxic properties have been investigated.{{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}}{{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}}{{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}}
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,{{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 }} inhibition of voltage-gated sodium and calcium channels, and monoamine oxidase B reversible inhibition are additional pharmacological actions that have been reported for kavalactones.{{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 }}
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,{{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}} particularly from extracts, as opposed to whole root powders.
Compounds
{{see also|Flavokavain}}
At least 18 different kavalactones are known, with methysticin being the first identified.
{{ 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
}}
Multiple analogues, such as ethysticin, have also been isolated.
{{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
}}
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.{{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}}
| 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 |
{{General kavalactone structures}}
Biosynthesis
The kavalactone biosynthetic pathway in Piper methysticum was described in 2019.{{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 | hdl=1721.1/124692 | s2cid=198139136 | hdl-access=free }}
See also
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
{{Kava}}
{{Natural phenol}}
{{GABAAR PAMs}}
Category:Monoamine oxidase inhibitors