Kavalactone Explained

Kavalactones are a class of lactone compounds found in kava roots and Alpinia zerumbet (shell ginger).^[1] Some kavalactones are bioactive.^{[2] [3]}

Bioactivity

Kava extract interacts with many pharmaceuticals and herbal medications. In human volunteers, in vivo inhibition includes CYP1A2^[4] and CYP2E1^[5] through use of probe drugs to measure inhibition.

Research

Its anxiolytic and hepatotoxicity activities have been investigated.^{[6] [7] [8]}

The major kavalactones (except for desmethoxyyangonin) potentiate GABA_A receptors, which may underlie the anxiolytic and sedative properties of kava. Further, inhibition of the reuptake of norepinephrine and dopamine, binding to the CB₁ receptor,^[9] inhibition of voltage-gated sodium and calcium channels, and monoamine oxidase B reversible inhibition are additional pharmacological actions that have been reported for kavalactones.^[10]

Kavalactone-type compounds may help protect against high glucose induced cell damage.^[2]

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,^{[7] [11]} particularly from extracts, as opposed to whole root powders.

Compounds

See also: Flavokavain. At least 18 different kavalactones are known,^[1] with methysticin being the first identified.^[12] Multiple analogues, such as ethysticin, have also been isolated.^[13] 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.^[14]

Kavalactones

Name	Structure	R1	R2	R3	R4
Yangonin	1	-OCH3	-H	-H	-H
10-methoxyyangonin	1	-OCH3	-H	-OCH3	-H
11-methoxyyangonin	1	-OCH3	-OCH3	-H	-H
11-hydroxyyangonin	1	-OCH3	-OH	-H	-H
Desmethoxyyangonin	1	-H	-H	-H	-H
11-methoxy-12-hydroxydehydrokavain	1	-OH	-OCH3	-H	-H
7,8-dihydroyangonin	2	-OCH3	-H	-H	-H
Kavain	3	-H	-H	-H	-H
5-hydroxykavain	3	-H	-H	-H	-OH
5,6-dihydroyangonin	3	-OCH3	-H	-H	-H
7,8-dihydrokavain	4	-H	-H	-H	-H
5,6,7,8-tetrahydroyangonin	4	-OCH3	-H	-H	-H
5,6-dehydromethysticin	5	-O-CH2-O-		-H	-H
Methysticin	7	-O-CH2-O-		-H	-H
7,8-dihydromethysticin	8	-O-CH2-O-		-H	-H

Biosynthesis

The kavalactone biosynthetic pathway in Piper methysticum was described in 2019.^[15]

See also

• Pipermethystine

External links

• Web site: NIH Kava Chemistry & Toxicology, Executive Summary .
• The great kava boom: how Fiji's beloved psychoactive brew is going global The Guardian, 2020

Notes and References

1. 10.1055/s-0040-1706044 . A Review on Synthetic Approaches towards Kavalactones . 2021 . Tadiparthi . Krishnaji . Anand . Pragya . Synthesis . 53 . 19 . 3469–3484 . 236392304 .
2. Kavalactones isolated from Alpinia zerumbet (Pers.) Burtt. Et Smith with protective effects against human umbilical vein endothelial cell damage induced by high glucose . 10.1080/14786419.2021.2023866 . 2022 . You . Hualin . He . Min . Pan . Di . Fang . Guanqin . Chen . Yan . Zhang . Xu . Shen . Xiangchun . Zhang . Nenling . Natural Product Research . 36 . 22 . 5740–5746 . 34989299 . 245771677 .
3. Inhibition of Human Cytochrome P450 Activities by Kava Extract and Kavalactones. Drug Metabolism and Disposition . 30 . 11 . 1153–1157 . James M. Mathews . Amy S. Etheridge . Sherry R. Black . 10.1124/dmd.30.11.1153 . 2002 . 12386118 .
4. Russmann . S . Lauterburg . B . Barguil . Y . Choblet . E . Cabalion . P . Rentsch . K . Wenk . M . 2005 . Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: Protective effect against environmental carcinogens? . . en . 77 . 5 . 453–454 . 10.1016/j.clpt.2005.01.021. 15900292 . 36009940 .
5. Gurley . B . Gardner . S . Hubbard . M . Williams . D . Gentry . W . Khan . I . Shah . A . 2005 . In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes . . en . 77 . 5 . 415–426 . 10.1016/j.clpt.2005.01.009 . 1894911 . 15900287.
6. Sarris. Jerome. LaPorte. Emma. Schweitzer. Isaac. 2011-01-01. Kava: A Comprehensive Review of Efficacy, Safety, and Psychopharmacology. Australian & New Zealand Journal of Psychiatry. en. 45. 1. 27–35. 10.3109/00048674.2010.522554. 21073405. 42935399.
7. 21756963. 2011. Teschke. R. Proposal for a kava quality standardization code. Food and Chemical Toxicology. 49. 10. 2503–16. Lebot. V. 10.1016/j.fct.2011.06.075.
8. 4325077. 2013. Wang. J. 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 of Food Science and Technology. 52. 2. 1164–1169. Qu. W. Bittenbender. H. C.. Li. Q. X.. 10.1007/s13197-013-1047-2. 25694734.
9. Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V . Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand . Pharmacol. Res. . 66 . 2 . 163–9 . 2012 . 22525682 . 10.1016/j.phrs.2012.04.003 .
10. Singh YN, Singh NN . Therapeutic potential of kava in the treatment of anxiety disorders . CNS Drugs . 16 . 11 . 731–43 . 2002 . 12383029 . 10.2165/00023210-200216110-00002. 34322458 .
11. 21442674. 2011. Teschke. R. Kava and kava hepatotoxicity: Requirements for novel experimental, ethnobotanical and clinical studies based on a review of the evidence. Phytotherapy Research. 25. 9. 1263–74. Qiu. S. X.. Xuan. T. D.. Lebot. V. 10.1002/ptr.3464. 19142750.
12. Naumov . P.. Dragull . K.. Yoshioka . M.. Tang . C.-S.. Ng . S. W. . Structural Characterization of Genuine (-)-Pipermethystine, (-)-Epoxypipermethystine, (+)-Dihydromethysticin and Yangonin from the Kava Plant (Piper methysticum). Natural Product Communications. 2008. 3. 8. 1333–1336. 10.1177/1934578X0800300819. 92030132. free.
13. Shulgin . A. . The narcotic pepper - the chemistry and pharmacology of Piper methysticum and related species . Bulletin on Narcotics . 2 . 1973 . 59–74 .
14. Web site: Kava (Piper methysticum): Pharmacodynamics/Kinetics. Sigma-Aldrich Co. LLC. 2010.
15. Pluskal . Tomáš . Torrens-Spence . Michael P. . Fallon . Timothy R. . De Abreu . Andrea . Shi . Cindy H. . Weng . Jing-Ke . The biosynthetic origin of psychoactive kavalactones in kava . Nature Plants . Springer Science and Business Media LLC . 5 . 8 . 2019-07-22 . 2055-0278 . 10.1038/s41477-019-0474-0 . 867–878. 31332312 . 1721.1/124692 . 198139136 . free .