In Vitro Toxicity of Kava Alkaloid, Pipermethystine, in HepG2 Cells Compared to Kavalactones

• Published in: Toxicological sciences 2004-05, Vol.79 (1), p.106-111
• Main Authors: Nerurkar, Pratibha V., Dragull, Klaus, Tang, Chung-Shih
• Format: Article
• Language: English
• Subjects: 8-dihydromethysticin; Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - toxicity; Animals; apoptosis; Apoptosis - drug effects; Caspases - drug effects; Cell Line, Tumor; desmethoxyyangonin; Dietary Supplements - toxicity; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Humans; kava; Kava - chemistry; Kava - metabolism; Kava - toxicity; kavalactones; Lactones - chemistry; Lactones - isolation & purification; Lactones - toxicity; piper methysticum; pipermethystine; Plant Extracts - chemistry; Plant Extracts - toxicity; Plant Leaves - chemistry; Plant Stems - adverse effects; Plant Stems - chemistry; Pyridones - chemistry; Pyridones - isolation & purification; Pyridones - toxicity; Pyrones - chemistry; Pyrones - metabolism; Pyrones - toxicity; Time Factors
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfh067

Kava herbal supplements have been recently associated with acute hepatotoxicity, leading to the ban of kava products in approximately a dozen countries around the world. It is suspected that some alkaloids from aerial kava may have contributed to the problem. Traditionally, Pacific Islanders use primarily the underground parts of the shrub to prepare the kava beverage. However, some kava herbal supplements may contain ingredients from aerial stem peelings. The aim of this study was to test the in vitro effects of a major kava alkaloid, pipermethystine (PM), found mostly in leaves and stem peelings, and kavalactones such as 7,8-dihydromethysticin (DHM) and desmethoxyyangonin (DMY), which are abundant in the roots. Exposure of human hepatoma cells, HepG2, to 100 μM PM caused 90% loss in cell viability within 24 h, while 50 μM caused 65% cell death. Similar concentrations of kavalactones did not affect cell viability for up to 8 days of treatment. Mechanistic studies indicate that, in contrast to kavalactones, PM significantly decreased cellular ATP levels, mitochondrial membrane potential, and induced apoptosis as measured by the release of caspase-3 after 24 h of treatment. These observations suggest that PM, rather than kavalactones, is capable of causing cell death, probably in part by disrupting mitochondrial function. Thus, PM may contribute to rare but severe hepatotoxic reactions to kava.