Methysticin

 ( Ethers ) 

Methysticin is one of the six major found in the kava plant. It enhances the activity of the GABAA receptor, acting as a positive modulator without affecting the benzodiazepine binding site. This effect is attributed to structural features such as its angular lactone ring and is similar in strength to other kavalactones like kavain and dihydromethysticin. Methysticin also induces the liver enzyme CYP1A1, which plays a role in the toxification of benzoapyrene into a highly carcinogenic metabolite, although such induction has not been observed in vivo in humans or animals. Additionally, methysticin is a mechanism-based inactivator of CYP2C9, irreversibly inhibiting the enzyme through NADPH-dependent reactive intermediates, suggesting potential interactions with medications metabolized by CYP2C9.

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Pharmacology It enhances the binding activity of the GABA_A receptor. Specifically, at a concentration of 0.1 micromolar, (+)-methysticin increases the binding of the receptor ligand ³Hbicuculline 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 ³Hflunitrazepam, 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)pyrene|benzo[ apyrene]] into [(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide|(+)-benzo[ apyrene-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 enzymes. It was found to strongly and irreversibly inhibit CYP2C9 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 or glutathione. 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, CYP2C9, and CYP3A4 enzymes were involved in methysticin bioactivation. 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 /ref>

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