Research

Characterization of the Metabolic Rates of Kavain, Dihydrokavain, and Desmethoxyyangonin in Mouse Liver Microsome Cells

Principal Investigator: Dr. Chennguo Xing Department: Medicinal Chemistry at the College of Pharmacy

Introduction to Kava

In recent years, Kava (Piper methysticum) has gained popularity in the United States as both a recreational beverage and a dietary supplement. Kava has traditionally been used in Pacific communities for its relaxing effects, and recent studies indicate that kava could be a potential prevention agent of lung tumorigenesis (Bian et al., 2020). Kavalactones are the active ingredients in kava, and it has been discovered that some kavalactones are more bioavailable than others (Kanumuri et al., 2022). While there have been preliminary metabolic studies of a few of the major kavalactones, namely kavain, methysticin, and desmethoxyyangonin (Fu et al., 2012), the analysis of desmethoxyyangonin is incomplete as its major metabolite has not been detected nor quantified in past studies. Currently, there has been limited research in the metabolism of other kavalactones. Due to the variability in the rate of metabolism of structurally similar kavalactones, further metabolic studies are needed to better understand the differences in bioavailability of kavalactones to accurately assess their safety and toxicity (Bian et al., 2020).

6 main naturally occuring kavalactones

The focus of this project is to quantify three of the major kavalactones—kavain, dihydrokavain, and desmethoxyyangonin—and their respective metabolites in mouse liver microsomes. These kavalactones have been chosen because they have nearly identical structures, except for the presence or absence of alkene bonds. Studying the metabolism of kavain, dihydrokavain, and desmethoxyyangonin is crucial in understanding the differences in bioavailability of kavalactones. This will help inform future decisions about which kavalactones are the safest and most effective for human use.

Methods

Kavalactones were incubated with mouse liver microsomes to evaluate their metabolic stability. A kavalactone mixture was first prepared in methanol and pre-incubated with potassium phosphate buffer and mouse liver microsomes. The reaction was initiated by adding a NADPH-regenerating system and incubated at physiological temperature. Aliquots were collected at multiple time points, quenched with ice-cold methanol, and centrifuged. Supernatants were dried, reconstituted, and analyzed using high-performance liquid chromatography (HPLC) to quantify kavalactone concentration over time.

Visualization of Cytochrome P450, the major enzyme responsible for kavalactone metabolism

I began kavalactone synthesis in April of 2024, and I shifted to developing the mouse liver microsome metabolic assay in January of 2025. My responsibilities include synthesizing and purifying the kavalactones for analysis, creating a metabolic protocol which optimizes conditions for the CYP450 enzyme and kavalactones, performing the metabolic assay, and performing data analysis using HPLC.

References

Bian, T., Corral, P., Wang, Y., Botello, J., Kingston, R., Daniels, T., … Xing, C. (2020). Kava as a clinical nutrient: Promises and challenges. Nutrients, 12(10), 3044. doi:10.3390/nu12103044

Fu, S., Rowe, A., & Ramzan, I. (2012). Kavalactone metabolism in the isolated perfused rat liver. Phytotherapy Research: PTR, 26(12), 1813–1816. doi:10.1002/ptr.4656

Kanumuri, S. R. R., Mamallapalli, J., Nelson, R., McCurdy, C. R., Mathews, C. A., Xing, C., & Sharma, A. (2022). Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers. Journal of Ethnopharmacology, 297(115514), 115514. doi: 10.1016/j.jep.2022.115514

Nelson, R., McCurdy, C. R., Mathews, C. A., Xing, C., & Sharma, A. (2022). Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers. Journal of Ethnopharmacology, 297(115514), 115514. doi: 10.1016/j.jep.2022.115514

Simmons, H. (2019, February 26). What are Cytochrome P450 (CYP) Enzymes? News-Medical. Retrieved August 29, 2025, from https://www.news-medical.net/life-sciences/What-are-Cytochrome-P450-Enzymes.aspx

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