Methysticin is one of the six major

kavalactone Kavalactones are a class of lactone compounds found in kava roots and ''Alpinia zerumbet'' (shell ginger) and in several Gymnopilus, Phellinus and Inonotus fungi. Some kavalactones are bioactive. They are responsible for the psychoactive, analges ...

s found in the

kava Kava or kava kava (''Piper methysticum'': Latin 'pepper' and Latinized Ancient Greek, Greek 'intoxicating') is a plant in the Piperaceae, pepper family, native to the Pacific Islands. The name ''kava'' is from Tongan language, Tongan and Marqu ...

plant. It enhances the activity of the GABA_A receptor, acting as a positive modulator without affecting the

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

binding site. This effect is attributed to structural features such as its angular lactone ring and is similar in strength to other

kavalactones Kavalactones are a class of lactone compounds found in kava roots and '' Alpinia zerumbet'' (shell ginger) and in several Gymnopilus, Phellinus and Inonotus fungi. Some kavalactones are bioactive. They are responsible for the psychoactive, analg ...

like kavain and dihydromethysticin. Methysticin also induces the liver enzyme

CYP1A1 Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the ''CYP1A1'' gene. The protein is a member of the cytochrome P450 superfamily of enzymes. Function Metabolism of xenobiotics and drugs CYP1A1 is ...

, which plays a role in the toxification of benzo yrene into a highly

carcinogenic A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

, although such induction has not been observed

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

in humans or animals. Additionally, methysticin is a mechanism-based inactivator of

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

, irreversibly inhibiting the enzyme through NADPH-dependent reactive intermediates, suggesting potential interactions with medications metabolized by CYP2C9.

Pharmacology

It enhances the binding activity of the GABA_A receptor. Specifically, at a concentration of 0.1

micromolar Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a s ...

, (+)-methysticin increases the binding of the receptor ligand �Hicuculline methochloride by approximately 18% to 28%, indicating it acts as a positive modulator of the GABA_A receptor. This modulatory effect is similar in strength to related kavapyrones such as (+)-kavain and (+)-dihydromethysticin. Importantly, methysticin’s effect is not due to interaction with the benzodiazepine receptor, as it does not influence the binding of �H lunitrazepam, which is a benzodiazepine receptor ligand. Structural features, such as the angular lactone ring present in methysticin and other enolides, are crucial for this activity. Overall, methysticin enhances GABA_A receptor function through a mechanism distinct from that of benzodiazepines, contributing to the neuroactive properties of kava. Methysticin induces the function of the hepatic enzyme CYP1A1. This enzyme is involved in the toxification of benzo 'a''yrene into (+)-benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide, a highly carcinogenic substance. Another related compound is dihydromethysticin, which also induces the function of CYP1A1. No report so far has described enhancement of CYP1A1 expression in animals or humans in vivo from any constituent of kava. It was studied for its effects on

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzymes. It was found to strongly and irreversibly inhibit

in a time-, concentration-, and NADPH-dependent manner, with ~85% inhibition at 50 μM. Kinetic analysis revealed a KI of 13.32 μM, kinact of 0.054 min⁻¹, and a half-life of inactivation around 12.8 minutes. The inhibition was partially prevented by sulfaphenazole (a CYP2C9 inhibitor), but not by antioxidants like

catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting ...

glutathione Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...

. Evidence suggests the involvement of reactive intermediates—a carbene (since K₃Fe(CN)₆ restored some activity) and an NADPH-dependent ortho-quinone trapped by glutathione.

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

, and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

enzymes were involved in methysticin

bioactivation In chemistry and biology, activation is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...

. Overall, methysticin acts as a mechanism-based inactivator of CYP2C9 through reactive intermediate formation.Zhang, Q., Liu, H., Wu, D., Yu, H., Wang, K., Jiao, W., & Zhao, X. (2022). Methysticin Acts as a Mechanism-Based Inactivator of Cytochrome P450 2C9. ''Chemical Research in Toxicology'', 35(6), 1117–1124. https://doi.org/10.1021/acs.chemrestox.2c00098

References

{{GABAAR PAMs Ethers Kavalactones Benzodioxoles Alkene derivatives GABAA receptor positive allosteric modulators Norepinephrine reuptake inhibitors Calcium channel blockers Sodium channel blockers Monoamine oxidase inhibitors